Pathways to adolescent social anxiety: Testing interactions between neural social reward function and perceived social threat in daily life.

Recent theories suggest that for youth highly sensitive to incentives, perceiving more social threat may contribute to social anxiety (SA) symptoms. In 129 girls (ages 11-13) oversampled for shy/fearful temperament, we thus examined how interactions between neural responses to social reward (vs. neutral) cues (measured during anticipation of peer feedback) and perceived social threat in daily peer interactions (measured using ecological momentary assessment) predict SA symptoms two years later. No significant interactions emerged when neural reward function was modeled as a latent factor. Secondary analyses showed that higher perceived social threat was associated with more severe SA symptoms two years later only for girls with higher basolateral amygdala (BLA) activation to social reward cues at baseline. Interaction effects were specific to BLA activation to social reward (not threat) cues, though a main effect of BLA activation to social threat (vs. neutral) cues on SA emerged. Unexpectedly, interactions between social threat and BLA activation to social reward cues also predicted generalized anxiety and depression symptoms two years later, suggesting possible transdiagnostic risk pathways. Perceiving high social threat may be particularly detrimental for youth highly sensitive to reward incentives, potentially due to mediating reward learning processes, though this remains to be tested.

Neural activity during negative self-evaluation is associated with negative self-concept and depressive symptoms in adolescent girls.

Self-concept becomes reliant on social comparison, potentially leading to excessive self-focused attention, persistently negative self-concept and increased risk for depression during early adolescence. Studies have implicated neural activation in cortical midline brain structures in self-related information processing, yet it remains unclear how this activation may underlie subjective self-concept and links to depression in adolescence. We examined these associations by assessing neural activity during negative vs. positive self-referential processing in 39 11-to-13-year-old girls. During a functional neuroimaging task, girls reported on their perceptions of self-concept by rating how true they believed positive and negative personality traits were about them. Girls reported on depressive symptoms at the scan and 6 months later. Activation in the dorsomedial and ventrolateral prefrontal cortexes (dMPFC; VLPFC), and visual association area was significantly associated with subjective self-concept and/or depressive symptoms at the scan or 6 months later. Exploratory models showed higher activation in the dMPFC to Self-negative > Self-positive was indirectly associated with concurrent depressive symptoms through more negative self-concept. Higher activation in the visual association area to Self-positive > Self-negative was associated with lower depressive symptoms at follow-up through more positive self-concept. Findings highlight how differential neural processing of negative versus positive self-relevant information maps onto perceptions of self-concept and adolescent depression.

Subgenual Anterior Cingulate Cortex Reactivity to Rejection Vs. Acceptance Predicts Depressive Symptoms among Adolescents with an Anxiety History.

OBJECTIVE: The goal of this study was to examine whether neural sensitivity to negative peer evaluation conveys risk for depression among youth with a history of anxiety. We hypothesized that brain activation in regions that process affective salience in response to rejection, relative to acceptance, from virtual peers would predict depressive symptoms 1 year later and would be associated with ecological momentary assessment (EMA) reports of peer connectedness. METHOD: Participants were 38 adolescents ages 11-16 (50% female) with a history of anxiety, recruited from a previous clinical trial. The study was a prospective naturalistic follow-up of depressive symptoms assessed 2 years (Wave 2) and 3 years (Wave 3) following treatment. At Wave 2, participants completed the Chatroom Interact Task during neuroimaging and 16 days of EMA. RESULTS: Controlling for depressive and anxiety symptoms at Wave 2, subgenual anterior cingulate (sgACC; ß = .39, p = .010) activation to peer rejection (vs. acceptance) predicted depressive symptoms at Wave 3. SgACC activation to rejection (vs. acceptance) was highly negatively correlated with EMA reports of connectedness with peers in daily life (r = - .71, p < .001). CONCLUSION: Findings suggest that elevated sgACC activation to negative, relative to positive, peer evaluation may serve as a risk factor for depressive symptoms among youth with a history of anxiety, perhaps by promoting vigilance or reactivity to social evaluative threats. SgACC activation to simulated peer evaluation appears to have implications for understanding how adolescents experience their daily social environments in ways that could contribute to depressive symptoms.

Emotional Interference in Early Adolescence: Positive Reinforcement Modulates the Behavioral and Neural Effects of Negative Emotional Distracters.

Limited research has examined functioning within fronto-limbic systems subserving the resistance to emotional interference in adolescence despite evidence indicating that alterations in these systems are implicated in the developmental trajectories of affective disorders. This study examined the functioning of fronto-limbic systems subserving emotional interference in early adolescence and whether positive reinforcement could modulate these systems to promote resistance to emotional distraction. Fifty healthy early adolescents (10-13 years old) completed an emotional delayed working memory (WM) paradigm in which no distractors (fixation crosshair) and emotional distracters (neutral and negative images) were presented with and without positive reinforcement for correct responses. WM accuracy decreased with negative distracters relative to neutral distracters and no distracters, and activation increased in amygdala and prefrontal cortical (PFC) regions (ventrolateral, dorsomedial, ventromedial, and subgenual anterior cingulate) with negative distracters compared with those with no distracters. Reinforcement improved performance and reduced activation in the amygdala, dorsomedial PFC, and ventrolateral PFC. Decreases in amygdala activation to negative distracters due to reinforcement mediated observed decreases in reaction times. These findings demonstrate that healthy adolescents recruit similar fronto-limbic systems subserving emotional interference as adults and that positive reinforcement can modulate fronto-limbic systems to promote resistance to emotional distraction.

Neural Responses to Social Reward Predict Depressive Symptoms in Adolescent Girls During the COVID-19 Pandemic.

OBJECTIVE: Adolescent depression is increasing during the COVID-19 pandemic, possibly related to dramatic social changes. Individual-level factors that contribute to social functioning, such as temperament and neural reactivity to social feedback, may confer risk for or resilience against depressive symptoms during the pandemic. METHODS: Ninety-three girls (12-17 years) oversampled for high shy/fearful temperament were recruited from a longitudinal study for a follow-up COVID-19 study. During the parent study (2016-2018), participants completed a functional magnetic resonance imaging task eliciting neural activity to performance-related social feedback. Depressive symptoms were assessed during the parent study and COVID-19 follow-up (April-May 2020). In 65 participants with complete data, we examined how interactions between temperament and neural activation to social reward or punishment in a socio-affective brain network predict depressive symptoms during COVID-19. RESULTS: Depressive symptoms increased during COVID-19. Significant interactions between temperament and caudate, putamen, and insula activation to social reward were found. Girls high in shy/fearful temperament showed negative associations between neural activation to social reward and COVID-19 depressive symptoms, whereas girls lower in shy/fearful temperament showed positive associations. CONCLUSIONS: Girls high in shy/fearful temperament with reduced neural activation to social reward may be less likely to engage socially, which could be detrimental during the pandemic when social interactions are limited. In contrast, girls lower in shy/fearful temperament with heightened neural reactivity to social reward may be highly motivated to engage socially, which could also be detrimental with limited social opportunities. In both cases, improving social connection during the pandemic may attenuate or prevent depressive symptoms.

Peer Connectedness and Pre-Existing Social Reward Processing Predicts U.S. Adolescent Girls' Suicidal Ideation During COVID-19.

There is major concern about the impact of the COVID-19 pandemic on adolescent suicidal ideation (SI) and peer relationships. We investigated (1) rates of SI and (2) the extent to which peer connectedness and pre-existing neural activation to social reward predicted SI during the initial stay-at-home orders of the pandemic (April-May 2020) in a longitudinal sample of adolescent girls (N = 93; Mage  = 15.06; 69% White non-Hispanic). Daily diary and fMRI methods were used to assess peer connectedness and neural activation to social reward, respectively. Nearly 40% of girls endorsed SI during the initial stay-at-home orders. Greater peer connectedness and neural responsivity to anticipated social reward were associated with a reduced odds of SI during the pandemic among girls.

Pupillary and affective responses to maternal feedback and the development of borderline personality disorder symptoms.

Etiological models propose that a biological vulnerability to emotional reactivity plays an important role in the development of borderline personality disorder (BPD). However, the physiological and phenomenological components of emotional reactivity that predict the course of BPD symptoms in adolescence are poorly understood. This prospective study examines pupillary and affective responses to maternal feedback as predictors of BPD symptom development in adolescent girls over 18 months. Fifty-seven 16-year-old girls completed a laboratory task in which they heard recorded clips of their own mothers making critical or praising statements about them, as well as neutral statements that did not pertain to them. Changes in girls' pupil dilation and subjective affect were assessed throughout the task. The results demonstrated that greater pupillary response to maternal criticism predicted increases in BPD symptoms over time. In addition, greater pupillary and positive affective responses to maternal praise were associated with higher BPD symptoms at age 16 and faster decreases in BPD symptoms over time, but only among girls who heard clips that were rated by independent observers as less praising. The results suggest that emotional reactivity can serve as either a risk or a protective factor depending on context, with differential effects of reactivity to criticism versus praise.

Negative emotional reactivity as a marker of vulnerability in the development of borderline personality disorder symptoms.

Negative emotionality is a distinguishing feature of borderline personality disorder (BPD). However, this person-level characteristic has not been examined as a marker of vulnerability in the development of this disorder. The current study utilized a multimethod approach to examine the interplay between negative emotional reactivity and cumulative exposure to family adversity on the development of BPD symptoms across 3 years (ages 16-18) in a diverse, at-risk sample of adolescent girls (N = 113). A latent variable of negative emotional reactivity was created from multiple assessments at age 16: self-report, emotion ratings to stressors from ecological assessments across 1 week, and observer-rated negative affectivity during a mother-daughter conflict discussion task. Exposure to family adversity was measured cumulatively between ages 5 and 16 from annual assessments of family poverty, single parent household, and difficult life circumstances. The results from latent growth curve models demonstrated a significant interaction between negative emotional reactivity and family adversity, such that exposure to adversity strengthened the association between negative emotional reactivity and BPD symptoms. In addition, family adversity predicted increasing BPD symptoms during late adolescence. These findings highlight negative emotional reactivity as a marker of vulnerability that ultimately increases risk for the development of BPD symptoms.

Depressed Adolescents' Pupillary Response to Peer Acceptance and Rejection: The Role of Rumination.

Heightened emotional reactivity to peer feedback is predictive of adolescents' depression risk. Examining variation in emotional reactivity within currently depressed adolescents may identify subgroups that struggle the most with these daily interactions. We tested whether trait rumination, which amplifies emotional reactions, explained variance in depressed adolescents' physiological reactivity to peer feedback, hypothesizing that rumination would be associated with greater pupillary response to peer rejection and diminished response to peer acceptance. Twenty currently depressed adolescents (12-17) completed a virtual peer interaction paradigm where they received fictitious rejection and acceptance feedback. Pupillary response provided a time-sensitive index of physiological arousal. Rumination was associated with greater initial pupil dilation to both peer rejection and acceptance, and diminished late pupillary response to peer acceptance trials only. Results indicate that depressed adolescents high on trait rumination are more reactive to social feedback regardless of valence, but fail to sustain cognitive-affective load on positive feedback.

Motivational and emotional influences on cognitive control in depression: A pupillometry study.

Depressed people perform poorly on cognitive tasks; however, under certain conditions they show intact cognitive performance, with physiological reactivity consistent with needing to recruit additional cognitive control. We hypothesized that this apparent compensation is driven by the presence of affective processes (e.g., state anxiety), which in turn are moderated by the depressed individual's motivational state. Clarifying these processes may help researchers identify targets for treatment that if addressed may improve depressed patients' cognitive functioning. To test this hypothesis, 36 participants with unipolar depression and 36 never-depressed controls completed a problem-solving task that was modified to elicit anxiety. The participants completed measures of motivation, anxiety, sadness, and rumination, while pupillary responses were continuously measured during problem-solving, as an index of cognitive control. Anxiety increased throughout the task for all participants, whereas both sadness and rumination were decreased during the task. In addition, anxiety more strongly affected planning accuracy in depressed participants than in controls, regardless of the participants' levels of motivation. In contrast, differential effects of anxiety on pupillary responses were observed as a function of depressed participants' levels of motivation. Consistent with the behavioral results, less-motivated and anxious depressed participants demonstrated smaller pupillary responses, whereas more highly motivated and anxious depressed participants demonstrated larger pupillary responses than did controls. Strong effects of sadness and rumination on cognitive control in depression were not observed. Thus, we conclude that anxiety inhibits the recruitment of cognitive control in depression and that a depressed individual's motivational state determines, in part, whether he or she is able to compensate by recruiting additional cognitive control.

Altered Lateral Prefrontal Cortex Functioning During Emotional Interference Resistance Is Associated With Affect Lability in Adults With Persisting Symptoms of Attention-Deficit/Hyperactivity Disorder From Childhood.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by inattention and/or impulsivity/hyperactivity. ADHD, especially when persisting into adulthood, often includes emotional dysregulation, such as affect lability; however, the neural correlates of emotionality in adults with heterogeneous ADHD symptom persistence remain unclear. METHODS: The present study sought to determine shared and distinct functional neuroanatomical profiles of neural circuitry during emotional interference resistance using the emotional face n-back task in adult participants with persisting (n = 47), desisting (n = 93), or no (n = 42) childhood ADHD symptoms while undergoing functional magnetic resonance imaging. RESULTS: Participants without any lifetime ADHD diagnosis performed significantly better (faster and more accurately) than participants with ADHD diagnoses on trials with high cognitive loads (2-back) that included task-irrelevant emotional distractors, tapping into executive functioning and emotion regulatory processes. In participants with persisting ADHD symptoms, more severe emotional symptoms were related to worse task performance. Heightened dorsolateral and ventrolateral prefrontal cortex activation was associated with more accurate and faster performance on 2-back emotional faces trials, respectively. Reduced activation was associated with greater affect lability in adults with persisting ADHD, and dorsolateral prefrontal cortex activation mediated the relationship between affect lability and task accuracy. CONCLUSIONS: These findings suggest that alterations in dorsolateral prefrontal cortex function associated with greater interference in cognitive processes from emotion could represent a marker of risk for problems with emotional dysregulation in individuals with persisting ADHD and thus represent a potential therapeutic target for those with greater emotional symptoms of ADHD.

Continuous theta burst stimulation to dorsomedial prefrontal cortex in young adults with depression: Changes in resting frontostriatal functional connectivity relevant to positive mood.

Depression is associated with diminished positive affect (PA), postulated to reflect frontostriatal reward circuitry disruptions. Depression has consistently been associated with higher dorsomedial prefrontal cortex (dmPFC) activation, a region that regulates PA through ventral striatum (VS) connections. Low PA in depression may reflect dmPFC's aberrant functional connectivity (FC) with the VS. To test this, we applied theta burst stimulation (TBS) to dmPFC in 29 adults with depression (79% female, Mage = 21.4, SD = 2.04). Using a randomized, counterbalanced design, we administered 3 types of TBS at different sessions: intermittent (iTBS; potentiating), continuous (cTBS; depotentiating), and sham TBS (control). We used neuronavigation to target personalized dmPFC targets based on VS-dmPFC FC. PA and negative affect (NA), and resting-state fMRI were collected pre- and post-TBS. We found no changes in PA or NA with time (pre/post), condition (iTBS, cTBS, sham), or their interaction. Functional connectivity (FC) between the nucleus accumbens and dmPFC showed a significant condition (cTBS, iTBS, and sham) by time (pre-vs. post-TBS) interaction, and post-hoc testing showed decreased pre-to post-TBS for cTBS but not iTBS or sham. For cTBS only, reduced FC pre/post stimulation was associated with increased PA (but not NA). Our findings lend support to the proposed mechanistic model of aberrant FC between the dmPFC and VS in depression and suggest a way forward for treating depression in young adults. Future studies need to evaluate multi-session TBS to test clinical effects.

CERT depletion predicts chemotherapy benefit and mediates cytotoxic and polyploid-specific cancer cell death through autophagy induction.

Chromosomal instability (CIN) has been implicated in multidrug resistance and the silencing of the ceramide transporter, CERT, promotes sensitization to diverse cytotoxics. An improved understanding of mechanisms governing multidrug sensitization might provide insight into pathways contributing to the death of CIN cancer cells. Using an integrative functional genomics approach, we find that CERT-specific multidrug sensitization is associated with enhanced autophagosome-lysosome flux, resulting from the expression of LAMP2 following CERT silencing in colorectal and HER2(+) breast cancer cell lines. Live cell microscopy analysis revealed that CERT depletion induces LAMP2-dependent death of polyploid cells following exit from mitosis in the presence of paclitaxel. We find that CERT is relatively over-expressed in HER2(+) breast cancer and CERT protein expression acts as an independent prognostic variable and predictor of outcome in adjuvant chemotherapy-treated patients with primary breast cancer. These data suggest that the induction of LAMP2-dependent autophagic flux through CERT targeting may provide a rational approach to enhance multidrug sensitization and potentiate the death of polyploid cells following paclitaxel exposure to limit the acquisition of CIN and intra-tumour heterogeneity.

Cognitive Processes in Response to Goal Failure: A Study of Ruminative Thought and its Affective Consequences.

Failure to make progress toward personal goals can lead to negative affective states, such as depression and anxiety. Past research suggests that rumination in response to goal failure may prolong and intensify those acute emotional responses, but that process remains unclear. We examined ruminative thought processes following experimentally manipulated exposure to past failures to attain advancement (promotion) goals and safety (prevention) goals. We predicted that priming of past promotion and prevention goal failures would lead individuals to think repetitively about these failures and that negative affect would be evoked by their recognition of their failures. Further, we predicted that when people experience a sufficient magnitude of negative affect, ruminative thought would intensify and prolong the negative affect associated with that type of goal failure. Results yielded strong support for our predictions regarding promotion goal failure and modest support for those regarding prevention goal failure.

Feeling bad about screwing up: emotion regulation and action monitoring in the anterior cingulate cortex.

This study examined neural features of emotional responses to errors. We specifically examined whether directed emotion regulation of negative emotion associated with error modulates action-monitoring functions of anterior cingulate cortex, including conflict monitoring, error processing, and error prevention. Seventeen healthy adults performed a continuous performance task during assessment by fMRI. In each block, participants were asked either to increase or decrease their negative emotional responses or to react naturally after error commission. Emotion regulation instructions were associated with modulation of rostral and dorsal anterior activity and of their effective connectivity following errors and conflict. Cingulate activity and connectivity predicted subsequent errors. These data may suggest that responses to errors are affected by emotion and that aspects of emotion and cognition are inextricably linked, even during a nominally cognitive task.

Impact of inflammatory bowel disease and high-dose steroid exposure on pupillary responses to negative information in pediatric depression.

OBJECTIVE: To better understand emotional information processing in pediatric inflammatory bowel disease (IBD) and its relationship with depression. Pediatric IBD is associated with higher rates of depression than seen in other physical diseases and in community samples. In systemic inflammation, proinflammatory cytokines have been implicated in altering activity in brain regions known to affect emotion processing and emotion regulation in depression. METHODS: We examined differences in pupillary responses as a marker of brain function in response to negative emotional information in youths (ages, 8-17 years) with IBD both with (n = 8) and without (n = 15) comorbid depression and who were receiving high-dose steroid treatment. We compared their responses to each other and to depressed youths without IBD (n = 20) and healthy youths (n = 22). RESULTS: Youths with IBD demonstrated greater pupillary responses to the initial presentation of negative emotional stimuli, regardless of their depression status (p = .05). In contrast, depressed youths, regardless of their IBD status, demonstrated a greater constriction of the pupil 10 seconds to 12 seconds after exposure to negative stimuli. This constriction was associated with greater depressive severity and lower albumin levels. CONCLUSIONS: IBD may be associated with increased sensitivity to negative emotional stimuli above and beyond depression diagnosis. Depressed youths potentially demonstrate affective blunting, emotional avoidance, or a failure to regulate emotion after exposure to negative emotional information. Thus, there seem to be unique contributions of medical disease and depression to physiological indications of emotional reactivity, but these factors do not seem to interact.

From scanners to cell phones: neural and real-world responses to social evaluation in adolescent girls.

While expanded use of neuroimaging seemed promising to elucidate typical and atypical elements of social sensitivity, in many ways progress in this space has stalled. This is in part due to a disconnection between neurobiological measurements and behavior outside of the laboratory. The present study uses a developmentally salient fMRI computer task and novel ecological momentary assessment protocol to examine whether early adolescent females (n = 76; ages 11-13) with greater neural reactivity to social rejection actually report greater emotional reactivity following negative interactions with peers in daily life. As hypothesized, associations were found between reactivity to perceived social threat in daily life and neural activity in threat-related brain regions, including the left amygdala and bilateral insula, to peer rejection relative to a control condition. Additionally, daily life reactivity to perceived social threat was associated with functional connectivity between the left amygdala and dorsomedial prefrontal cortex during rejection feedback. Unexpectedly, daily life social threat reactivity was also related to heightened amygdala and insula activation to peer acceptance relative to a control condition. These findings may inform key brain-behavior associations supporting sensitivity to social evaluation in adolescence.

"Don't judge me!": Links between in vivo attention bias toward a potentially critical judge and fronto-amygdala functional connectivity during rejection in adolescent girls.

During adolescence, increases in social sensitivity, such as heightened attentional processing of social feedback, may be supported by developmental changes in neural circuitry involved in emotion regulation and cognitive control, including fronto-amygdala circuitry. Less negative fronto-amygdala circuitry during social threat processing may contribute to heightened attention to social threat in the environment. However, "real-world" implications of altered fronto-amygdala circuitry remain largely unknown. In this study, we used multiple novel methods, including an in vivo attention bias task implemented using mobile eye-tracking glasses and socially interactive fMRI task, to examine how functional connectivity between the amygdala and prefrontal cortex (PFC) during rejection and acceptance feedback from peers is associated with heightened attention towards potentially critical social evaluation in a real-world environment. Participants were 77 early adolescent girls (ages 11-13) oversampled for shy/fearful temperament. Results support the reliability of this in vivo attention task. Further, girls with more positive functional connectivity between the right amygdala and anterior PFC during both rejection and acceptance feedback attended more to potentially critical social evaluation during the attention task. Findings could suggest that dysfunction in prefrontal regulation of the amygdala's response to salient social feedback supports heightened sensitivity to socially evaluative threat during adolescence.

The deubiquitylase USP9X controls ribosomal stalling.

When a ribosome stalls during translation, it runs the risk of collision with a trailing ribosome. Such an encounter leads to the formation of a stable di-ribosome complex, which needs to be resolved by a dedicated machinery. The initial stalling and the subsequent resolution of di-ribosomal complexes requires activity of Makorin and ZNF598 ubiquitin E3 ligases, respectively, through ubiquitylation of the eS10 and uS10 subunits of the ribosome. We have developed a specific small-molecule inhibitor of the deubiquitylase USP9X. Proteomics analysis, following inhibitor treatment of HCT116 cells, confirms previous reports linking USP9X with centrosome-associated protein stability but also reveals a loss of Makorin 2 and ZNF598. We show that USP9X interacts with both these ubiquitin E3 ligases, regulating their abundance through the control of protein stability. In the absence of USP9X or following chemical inhibition of its catalytic activity, levels of Makorins and ZNF598 are diminished, and the ribosomal quality control pathway is impaired.

MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.

KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995.