IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1-4. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies5-8-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.

Relationships Between Prenatal Cocaine Exposure, Cannabis-Use Onset and Emotional and Related Characteristics in Young/Emerging Adults.

Background: Exposure to substances in utero may have significant early-life consequences. Less is known about the effects in emerging adulthood, particularly regarding patterns of substance use and related characteristics.Objectives: In this study, we recruited emerging adults, followed since birth, who had been prenatally exposed, or not, to cocaine. Individuals reported on their cannabis, alcohol, and tobacco use, and measures of impulsivity, anhedonia, emotional regulation, and mental health were obtained. Comparisons were made between emerging adults with prenatal cocaine exposure and those without. Correlations were performed between psychological measures and substance use, and regression analyses were conducted to determine potential pathways by which such measures may relate to prenatal exposure or substance use.Results: Individuals with prenatal cocaine exposure (vs. those without) used cannabis at younger ages, reported greater cannabis-use severity, and demonstrated higher impulsivity, state anxiety, and alexithymia. Earlier age of onset of cannabis use was associated with higher impulsivity, state anxiety, alexithymia, and social and physical anhedonia. Cannabis-use age-of-onset mediated the relationship between prenatal cocaine-exposure status and state anxiety and between prenatal cocaine-exposure status and cannabis-use severity in emerging adulthood but not relationships between prenatal cocaine-exposure status and impulsivity or alexithymia in emerging adulthood. Findings suggest that adults with prenatal cocaine exposure may use cannabis at younger ages, which may relate to increased anxiety and more severe use.Conclusions: These findings suggest both mechanisms and possible intervention targets to improve mental health in emerging adults with prenatal cocaine exposure.

Modeling brain dynamics and gaze behavior: Starting point bias and drift rate relate to frontal midline theta oscillations.

Frontal midline theta oscillatory dynamics have been implicated as an important neural signature of inhibitory control. However, most proactive cognitive control studies rely on behavioral tasks where individual differences are inferred through button presses. We applied computational modeling to further refine our understanding of theta dynamics in a cued anti-saccade task with gaze-contingent eye tracking. Using a drift diffusion model, increased frontal midline theta power during high-conflict, relative to low-conflict, trials predicted a more conservative style of responding through the starting point (bias). During both high- and low-conflict trials, increases in frontal midline theta also predicted improvements in response efficiency (drift rate). Regression analyses provided support for the importance of the starting point bias, which was associated with frontal midline theta over the course of the task above-and-beyond both drift rate and mean reaction time. Our findings provide a more thorough understanding of proactive gaze control by linking trial-by-trial increases of frontal midline theta to a shift in starting point bias facilitating a more neutral style of responding.

Functional connectivity during tic suppression predicts reductions in vocal tics following behavior therapy in children with Tourette syndrome.

BACKGROUND: Comprehensive Behavioral Intervention for Tics (CBIT) is recommended as a first-line treatment for Tourette syndrome in children and adults. While there is strong evidence proving its efficacy, the mechanisms of reduction in tic severity during CBIT are still poorly understood. In a recent study, our group identified a functional brain network involved in tic suppression in children with TS. We reasoned that voluntary tic suppression and CBIT may share some mechanisms and thus we wanted to assess whether functional connectivity during tic suppression was associated with CBIT outcome. METHODS: Thirty-two children with TS, aged 8 to 13 years old, participated in a randomized controlled trial of CBIT v. a treatment-as-usual control condition. EEG was recorded during tic suppression in all participants at baseline and endpoint. We used a source-reconstructed EEG connectivity pipeline to assess functional connectivity during tic suppression. RESULTS: Functional connectivity during tic suppression did not change from baseline to endpoint. However, baseline tic suppression-related functional connectivity specifically predicted the decrease in vocal tic severity from baseline to endpoint in the CBIT group. Supplementary analyses revealed that the functional connectivity between the right superior frontal gyrus and the right angular gyrus was mainly driving this effect. CONCLUSIONS: This study revealed that functional connectivity during tic suppression at baseline predicted reduction in vocal tic severity. These results suggest probable overlap between the mechanisms of voluntary tic suppression and those of behavior therapy for tics.

Large-scale functional brain networks of maladaptive childhood aggression identified by connectome-based predictive modeling.

Disruptions in frontoparietal networks supporting emotion regulation have been long implicated in maladaptive childhood aggression. However, the association of connectivity between large-scale functional networks with aggressive behavior has not been tested. The present study examined whether the functional organization of the connectome predicts severity of aggression in children. This cross-sectional study included a transdiagnostic sample of 100 children with aggressive behavior (27 females) and 29 healthy controls without aggression or psychiatric disorders (13 females). Severity of aggression was indexed by the total score on the parent-rated Reactive-Proactive Aggression Questionnaire. During fMRI, participants completed a face emotion perception task of fearful and calm faces. Connectome-based predictive modeling with internal cross-validation was conducted to identify brain networks that predicted aggression severity. The replication and generalizability of the aggression predictive model was then tested in an independent sample of children from the Adolescent Brain Cognitive Development (ABCD) study. Connectivity predictive of aggression was identified within and between networks implicated in cognitive control (medial-frontal, frontoparietal), social functioning (default mode, salience), and emotion processing (subcortical, sensorimotor) (r = 0.31, RMSE = 9.05, p = 0.005). Out-of-sample replication (p < 0.002) and generalization (p = 0.007) of findings predicting aggression from the functional connectome was demonstrated in an independent sample of children from the ABCD study (n = 1791; n = 1701). Individual differences in large-scale functional networks contribute to variability in maladaptive aggression in children with psychiatric disorders. Linking these individual differences in the connectome to variation in behavioral phenotypes will advance identification of neural biomarkers of maladaptive childhood aggression to inform targeted treatments.

Frontal EEG asymmetry moderates the relation between borderline personality disorder features and feelings of social rejection in adolescents.

Although associations among borderline personality disorder (BPD), social rejection, and frontal EEG alpha asymmetry scores (FAA, a neural correlate of emotion regulation and approach-withdrawal motivations) have been explored in different studies, relatively little work has examined these relations during adolescence in the same study. We examined whether FAA moderated the relation between BPD features and rejection sensitivity following a validated social exclusion paradigm, Cyberball. A mixed, clinical-community sample of 64 adolescents (females = 62.5%; Mage = 14.45 years; SD = 1.6; range = 11-17 years) completed psychodiagnostic interviews and a self-report measure of BPD (Time 1). Approximately two weeks later (Time 2), participants completed a resting EEG recording followed by Cyberball. FAA moderated the relation between BPD features and overall feelings of rejection following Cyberball: individuals with greater relative left FAA had the highest and lowest feelings of social rejection depending on whether they had high and low BPD feature scores, respectively. Results remained after controlling for age, sex, gender, depression, and BPD diagnosis. These results suggest that FAA may moderate the relation between BPD features and social rejection, and that left frontal brain activity at rest may be differentially associated with those feelings in BPD. Findings are discussed in terms of the link between left frontal brain activity in the regulation and dysregulation of social approach behaviors, characteristic of BPD.

Emotional maltreatment and neglect impact neural activation upon exclusion in early and mid-adolescence: An event-related fMRI study.

Child maltreatment gives rise to atypical patterns of social functioning with peers which might be particularly pronounced in early adolescence when peer influence typically peaks. Yet, few neuroimaging studies in adolescents use peer interaction paradigms to parse neural correlates of distinct maltreatment exposures. This fMRI study examines effects of abuse, neglect, and emotional maltreatment (EM) among 98 youth (n = 58 maltreated; n = 40 matched controls) using an event-related Cyberball paradigm affording assessment of both social exclusion and inclusion across early and mid-adolescence (≤13.5 years, n = 50; >13.5 years, n = 48). Younger adolescents showed increased activation to social exclusion versus inclusion in regions implicated in mentalizing (e.g., superior temporal gyrus). Individual exposure-specific analyses suggested that neglect and EM coincided with less reduction of activation to social exclusion relative to inclusion in the dorsal anterior cingulate cortex/pre-supplementary motor area (dACC/pre-SMA) among younger versus older adolescents. Integrative follow-up analyses showed that EM accounted for this dACC/pre-SMA activation pattern over and above other exposures. Moreover, age-independent results within respective exposure groups revealed that greater magnitude of neglect predicted blunted exclusion-related activity in the parahippocampal gyrus, while EM predicted increased activation to social exclusion in the precuneus/posterior cingulate cortex.

Children's shyness and neural responses to social exclusion: Patterns of midfrontal theta power usually not observed until adolescence.

Adverse peer experiences, such as social exclusion, are known risks for socioemotional problems among shy youth. Yet, little is known about how shy children and adolescents process social exclusion in the brain and whether these responses are amplified in adolescence. Using the Cyberball task, we examined mediofrontal theta (4-7 Hz) event-related EEG spectral power during conditions of fair play and social exclusion in 122 participants (58 children, ages 10-12 years, and 64 adolescents, ages 14-17 years). Age effects of the task showed that adolescents displayed heightened theta power to both outright rejection and baseline "not my turn" events, whereas children showed higher theta power to rejection compared with "not my turn" events. Further results on individual differences showed that children with relatively higher levels of shyness displayed enhanced theta power to both rejection and "not my turn" events-a pattern that also was observed in adolescents. These findings suggest that a pattern of heightened neural sensitivity to both outright social exclusion and threats of exclusion, which is the norm by adolescence, also is observed in children with higher levels of shyness. The similar neural response pattern might be driven by salient social motivations that similarly modify the social cognition and behaviors of these groups and might reflect neural antecedents of rejection sensitivity.

Exclusion Expected? Cardiac Slowing Upon Peer Exclusion Links Preschool Parent Representations to School-Age Peer Relationships.

Attachment theory proposes that children's representations of interactions with caregivers guide information-processing about others, bridging interpersonal domains. In a longitudinal study (N = 165), preschoolers (Mage  = 5.19 years) completed the MacArthur Story Stem Battery to assess parent representations. At school-age (Mage  = 8.42 years), children played a virtual ballgame with peers who eventually excluded them to track event-related cardiac slowing, a physiological correlate of rejection, especially when unexpected. At both ages, parents and teachers reported on peer and emotional problems. During exclusion versus inclusion-related events, cardiac slowing was associated with greater positive parent representations and fewer emerging peer problems. Cardiac slowing served as a mediator between positive parent representations and peer problems, supporting a potential psychophysiological mechanism underlying the generalization of attachment-related representations to peer relationships.

Getting to the heart of food craving with resting heart rate variability in adolescents.

BACKGROUND: There is an epidemic of obesity in children and adolescents. Research into the self-regulatory factors that drive eating behavior is of critical importance. Food craving contributes to overeating and difficulty with weight loss and is strongly correlated with self-regulation. High-frequency heart rate variability (HF HRV) reflects parasympathetic activity and is positively associated with self-regulation. Few studies of HF HRV and food craving have been conducted in adolescents. The current study examined the association between HF HRV and food craving in a large-scale sample of healthy adolescents. METHOD: Electrocardiogram (ECG) was recorded in 134 healthy adolescents aged 10-17 during a 7-min resting state. Participants also completed the Food Craving Questionnaire-Trait (FCQ-T). The relative power of HF HRV was calculated. Association between HF HRV and food craving was examined in the context of sex and age. Next, the relative significance of all food craving subscales was considered in relation to HF HRV. RESULTS: HF HRV was inversely correlated with food craving, taking into account sex and age. Considering all the subscales of FCQ-T in relation to HF HRV, the "lack of control over eating" subscale accounted for the most significant variance. CONCLUSION: This was the first study to evaluate resting HRV and eating behaviors in a large-scale adolescent sample. HF HRV was negatively associated with food craving, with lower HF HRV correlating with higher food craving, especially in the context of diminished control over eating. HF HRV could be a potential biomarker for food craving and food-related self-regulation capacity, and therefore may aid weight management interventions.

Driving status of patients with generalized spike-wave on EEG but no clinical seizures.

Generalized spike-wave discharges (SWDs) are the hallmark of generalized epilepsy on the electroencephalogram (EEG). In clinically obvious cases, generalized SWDs produce myoclonic, atonic/tonic, or absence seizures with brief episodes of staring and behavioral unresponsiveness. However, some generalized SWDs have no obvious behavioral effects. A serious challenge arises when patients with no clinical seizures request driving privileges and licensure, yet their EEG shows generalized SWD. Specialized behavioral testing has demonstrated prolonged reaction times or missed responses during SWD, which may present a driving hazard even when patients or family members do not notice any deficits. On the other hand, some SWDs are truly asymptomatic in which case driving privileges should not be restricted. Clinicians often decide on driving privileges based on SWD duration or other EEG features. However, there are currently no empirically-validated guidelines for distinguishing generalized SWDs that are "safe" versus "unsafe" for driving. Here, we review the clinical presentation of generalized SWD and recent work investigating mechanisms of behavioral impairment during SWD with implications for driving safety. As a future approach, computational analysis of large sets of EEG data during simulated driving utilizing machine learning could lead to powerful methods to classify generalized SWD as safe vs. unsafe. This may ultimately provide more objective EEG criteria to guide decisions on driving safety in people with epilepsy.

EEG captures affective touch: CT-optimal touch and neural oscillations.

Tactile interactions are of developmental importance to social and emotional interactions across species. In beginning to understand the affective component of tactile stimulation, research has begun to elucidate the neural mechanisms that underscore slow, affective touch. Here, we extended this emerging body of work and examined whether affective touch (C tactile [CT]-optimal speed), as compared to nonaffective touch (non-CT-optimal speed) and no touch conditions, modulated EEG oscillations. We report an attenuation in alpha and beta activity to affective and nonaffective touch relative to the no touch condition. Further, we found an attenuation in theta activity specific to the affective, as compared to the nonaffective touch and no touch conditions. Similar to theta, we also observed an attenuation of beta oscillations during the affective touch condition, although only in parietal scalp sites. Decreased activity in theta and parietal-beta ranges may reflect attentional-emotional regulatory mechanisms; however, future work is needed to provide insight into the potential neural coupling between theta and beta and their specific role in encoding slow, tactile stimulation.

Community structure analysis of rejection sensitive personality profiles: A common neural response to social evaluative threat?

Monitoring social threat is essential for maintaining healthy social relationships, and recent studies suggest a neural alarm system that governs our response to social rejection. Frontal-midline theta (4-8 Hz) oscillatory power might act as a neural correlate of this system by being sensitive to unexpected social rejection. Here, we examined whether frontal-midline theta is modulated by individual differences in personality constructs sensitive to social disconnection. In addition, we examined the sensitivity of feedback-related brain potentials (i.e., the feedback-related negativity and P3) to social feedback. Sixty-five undergraduate female participants (mean age = 19.69 years) participated in the Social Judgment Paradigm, a fictitious peer-evaluation task in which participants provided expectancies about being liked/disliked by peer strangers. Thereafter, they received feedback signaling social acceptance/rejection. A community structure analysis was employed to delineate personality profiles in our data. Results provided evidence of two subgroups: one group scored high on attachment-related anxiety and fear of negative evaluation, whereas the other group scored high on attachment-related avoidance and low on fear of negative evaluation. In both groups, unexpected rejection feedback yielded a significant increase in theta power. The feedback-related negativity was sensitive to unexpected feedback, regardless of valence, and was largest for unexpected rejection feedback. The feedback-related P3 was significantly enhanced in response to expected social acceptance feedback. Together, these findings confirm the sensitivity of frontal midline theta oscillations to the processing of social threat, and suggest that this alleged neural alarm system behaves similarly in individuals that differ in personality constructs relevant to social evaluation.

STMN1 is Overexpressed in Adrenocortical Carcinoma and Promotes a More Aggressive Phenotype In Vitro.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics through inhibition of tubulin polymerization and promotion of microtubule depolymerization, which has been implicated in carcinogenesis and aggressive behavior in multiple epithelial malignancies. We aimed to evaluate expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype. METHODS: STMN1 was identified by RNA sequencing as a highly differentially expressed gene in human ACC samples compared with benign adrenal tumors. Expression was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical (IHC) staining of a tissue microarray (TMA) from two independent cohorts. The biologic relevance of STMN1 was investigated in NCI-H295R cells by lentivirus-mediated silencing. RESULTS: Differential gene expression demonstrated an eightfold increase in STMN1 messenger RNA (mRNA) in malignant compared with benign adrenal tissue. IHC showed significantly higher expression of STMN1 protein in ACC compared with normal and benign tissues. STMN1 knockdown in an ACC cell line resulted in decreased cell viability, cell-cycle arrest at G0/G1, and increased apoptosis in serum-starved conditions compared with scramble short hairpin RNA (shRNA) controls. STMN1 knockdown also decreased migration, invasion, and anchorage-independent growth compared with controls. CONCLUSIONS: STMN1 is overexpressed in human ACC samples, and knockdown of this target in vitro resulted in a less aggressive phenotype of ACC, particularly under serum-starved conditions. Further study is needed to investigate the feasibility of interfering with STMN1 as a potential therapeutic target.

Innovations in practice: group mindfulness for adolescent anxiety - results of an open trial.

BACKGROUND: Group Mindfulness Therapy (GMT) is a program tailored for adolescents that targets anxiety with mindfulness skills including present moment awareness, mindfulness in everyday life (breathing, eating, walking), body scan, loving-kindness, and self-acceptance. Youth with anxiety may benefit from mindfulness exercises precisely because they learn to redirect their mind, and presumably their attention, away from wandering in the direction of worry and negative self-appraisals and toward greater acceptance of internal states. This open trial assessed the feasibility and initial effectiveness of GMT in a school setting. METHOD: Twelve 6th and 7th grade adolescents with elevated anxiety [Screen for Child Anxiety Disorders (SCARED) ≥ 30] participated in GMT after school. Youth completed measures of anxiety and perceived stress and their parents completed measures of internalizing and externalizing behavior problems at pretreatment and posttreatment. We hypothesized that GMT would significantly reduce youth anxiety and stress. RESULTS: Significant improvements were observed in anxiety, internalizing, stress, and attention, with effect sizes ranging from .88 to 1.34. CONCLUSIONS: We demonstrate that GMT is feasible and acceptable to adolescents presenting with anxiety as a primary concern. We provide further support for the use of a mindfulness-based intervention for anxiety reduction. The group format suggests a cost-effective way to deliver services in a school setting.

Adolescent positive self, negative self: associated but dissociable?

Adolescence is a period of significant identity development and particular vulnerability to depression associated with negative self-evaluation. We investigated if increased depressive symptom severity was also associated with positive self-evaluation. We also considered pubertal developmental differences in positive and negative self-evaluation, and if these could reflect dissociated facets of the self. This cross-sectional sample consisted of healthy male and female adolescents (N = 109) aged 12-17 from the United States. Participants completed a self-referential encoding task, which required them to indicate if a single-word adjective was self-descriptive. We administered the Children's Depression Inventory, the Pubertal Development Scale, and the Child Narcissism Scale. Negative-word endorsement was significantly predicted by pubertal maturation level and depressive symptoms, but not by narcissism. Positive-word endorsement was significantly predicted by narcissism and negatively predicted by depressive symptoms, but not by pubertal maturation. In this typically developing sample, positive self-judgment does not vary across the pubertal range and is positively associated with narcissistic traits, and negatively associated with depressive symptom severity. Negative self-judgements are positively correlated with puberty and are associated with depressive symptom severity only. Our findings suggest that negative and positive aspects of the self are partially dissociable.

Commentary: The importance of exploring dose-dependent, subtype-specific, and age-related effects of maltreatment on the HPA axis and the mediating link to psychopathology. A response to Fisher (2017).

We greatly appreciate Dr. Fisher's commentary that provides an excellent backdrop and well-considered perspective on our findings. We agree that our results mesh well with previous work documenting hypocortisolism among youth who experienced early adversity, especially neglect. Moreover, as also perceptively noted by Dr. Fisher, our cross-sectional data provide support for the notion that hypocortisolism is not simply a transient phenomenon, but, rather, a persistent pattern characterizing maltreated youth. Specifically, the consistency of the between group effect (from age 9.69 onwards) on a multimonth index of cumulative cortisol and the dose-dependent gradient of cortisol secretion within the maltreated group, which was related to the number of subtypes and the length of exposure to maltreatment, lend weight to this view.

Reduced hair cortisol after maltreatment mediates externalizing symptoms in middle childhood and adolescence.

BACKGROUND: The enduring impact of childhood maltreatment on biological systems and ensuing psychopathology remains incompletely understood. Long-term effects of stress may be reflected in cumulative cortisol secretion over several months, which is now quantifiable via hair cortisol concentrations (HCC). We conducted a first comprehensive investigation utilizing the potential of hair cortisol analysis in a large sample of maltreated and nonmaltreated children and adolescents. METHOD: Participants included 537 children and adolescents (3-16 years; 272 females) with maltreatment (n = 245) or without maltreatment histories (n = 292). Maltreated subjects were recruited from child protection services (CPS; n = 95), youth psychiatric services (n = 56), and the community (n = 94). Maltreatment was coded using the Maltreatment Classification System drawing on caregiver interviews and complemented with CPS records. Caregivers and teachers reported on child mental health. HCC were assessed in the first 3 cm hair segment. RESULTS: Analyses uniformly supported that maltreatment coincides with a gradual and dose-dependent reduction in HCC from 9 to 10 years onwards relative to nonmaltreated controls. This pattern emerged consistently from both group comparisons between maltreated and nonmaltreated subjects (27.6% HCC reduction in maltreated 9-16-year-olds) and dimensional analyses within maltreated subjects, with lower HCC related to greater maltreatment chronicity and number of subtypes. Moreover, both group comparisons and dimensional analyses within maltreated youth revealed that relative HCC reduction mediates the effect of maltreatment on externalizing symptoms. CONCLUSIONS: From middle childhood onwards, maltreatment coincides with a relative reduction in cortisol secretion, which, in turn, may predispose to externalizing symptoms.

Gender-related Differences in Inhibitory Control and Sustained Attention among Adolescents with Prenatal Cocaine Exposure.

Adolescence and prenatal cocaine exposure can impact risk-taking. In this study, we evaluated risk-taking and gender-related differences in adolescents with prenatal cocaine exposure in terms of electrophysiological correlates of inhibitory control and sustained attention. No differences related to gender were found within measures of risk-taking, or electrophysiological response relating to risk-taking. Greater responses during inhibition versus attention trials support previous studies, with boys showing the largest responses. Gender-related differences were found when comparing the trials before and after frustration was induced, with greater initial attention indices for girls in both trial types and greater sustained attention for both genders during inhibition trials and for boys during attention trials. These data suggest neural correlates of response inhibition show important gender-related differences in this population. Considering these relationships allows us to further understand underlying processes among adolescents who, as a group, tend to be more inclined toward greater risk behaviors.

Social exclusion modulates event-related frontal theta and tracks ostracism distress in children.

Social exclusion is a potent elicitor of distress. Previous studies have shown that medial frontal theta oscillations are modulated by the experience of social exclusion. Using the Cyberball paradigm, we examined event-related dynamics of theta power in the EEG at medial frontal sites while children aged 8-12 years were exposed to conditions of fair play and social exclusion. Using an event-related design, we found that medial frontal theta oscillations (4-8Hz) increase during both early (i.e., 200-400ms) and late (i.e., 400-800ms) processing of rejection events during social exclusion relative to perceptually identical "not my turn" events during inclusion. Importantly, we show that only for the later time window (400-800ms) slow-wave theta power tracks self-reported ostracism distress. Specifically, greater theta power at medial frontal sites to "rejection" events predicted higher levels of ostracism distress. Alpha and beta oscillations for rejection events were unrelated to ostracism distress at either 200-400ms or 400-800ms time windows. Our findings extend previous studies by showing that medial frontal theta oscillations for rejection events are a neural signature of social exclusion, linked to experienced distress in middle childhood.