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.

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.

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.

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.

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.

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.

"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.

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.

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.

Reduced Activation in the Pallidal-Thalamic-Motor Pathway Is Associated With Deficits in Reward-Modulated Inhibitory Control in Adults With a History of Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) symptoms persist into adulthood and are associated with functional impairments. Neuroimaging studies of reward-modulated inhibitory control can identify potential objective markers of impairment and may deepen our understanding of why probands engage in costly behaviors leading to adverse outcomes. The study aimed to identify reward-modulated inhibitory control neural circuitries, their association with ADHD symptoms, and real-world implications of a decreased capacity to engage in reward-modulated inhibitory control. METHODS: A total of 106 adults (90% male) with rigorous childhood diagnoses of ADHD were scanned with functional magnetic resonance imaging during the Monetary Incentive Go/NoGo task. Adulthood symptoms of inattention and hyperactivity/impulsivity based on self- and informant report were assessed. The number of lifetime attempts taken to quit smoking were also assessed as an exemplar real-world outcome. RESULTS: Hyperactivity/impulsivity was negatively associated with activation in the pallidum and primary motor cortex when inhibiting a previously rewarded Go stimulus that yielded a small immediate reward in order to obtain a larger reward later on. Reduced recruitment of the pallidal-thalamic-motor circuit mediated the negative association between hyperactivity/impulsivity and reward-modulated inhibitory control accuracy. Reduced pallidum activation, in response to reward-modulated inhibitory control, was also associated with more attempts made to successfully quit smoking. CONCLUSIONS: Probands with persistent hyperactivity/impulsivity symptoms have alterations in brain regions that calculate the value of inhibiting an action that yields an immediate reward in order to obtain delayed larger rewards. This deficit results in poor inhibitory control on basic tasks and during real-world behaviors that rely on similar processes.

Identifying strategies to target the metabolic flexibility of tumours.

Plasticity of cancer metabolism can be a major obstacle to efficient targeting of tumour-specific metabolic vulnerabilities. Here, we identify the compensatory mechanisms following the inhibition of major pathways of central carbon metabolism in c-MYC-induced liver tumours. We find that, while inhibition of both glutaminase isoforms (Gls1 and Gls2) in tumours considerably delays tumourigenesis, glutamine catabolism continues, owing to the action of amidotransferases. Synergistic inhibition of both glutaminases and compensatory amidotransferases is required to block glutamine catabolism and proliferation of mouse and human tumour cells in vitro and in vivo. Gls1 deletion is also compensated for by glycolysis. Thus, co-inhibition of Gls1 and hexokinase 2 significantly affects Krebs cycle activity and tumour formation. Finally, the inhibition of biosynthesis of either serine (Psat1-KO) or fatty acid (Fasn-KO) is compensated for by uptake of circulating nutrients, and dietary restriction of both serine and glycine or fatty acids synergistically suppresses tumourigenesis. These results highlight the high flexibility of tumour metabolism and demonstrate that either pharmacological or dietary targeting of metabolic compensatory mechanisms can improve therapeutic outcomes.

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.

Positive affect between close friends: Brain-behavior associations during adolescence.

Identifying the neural correlates of positive interactions between friendship dyads may provide insights into mechanisms associated with adolescent social development. Forty-eight 14- to 18-year-old typically developing adolescents were video-recorded discussing a shared positive event with a close friend and subsequently viewed clips during an fMRI scan of that friend during the interaction and of an unfamiliar peer in a similar interaction. Adolescents also reported on their positive affect in daily life while with friends using ecological momentary assessment. We used multivariate repeated measures models to evaluate how positive affect with friends in the laboratory and in daily life was associated with neural response to friend and stranger positive and neutral clips. Adolescents who exhibited more positive affect when with friends in the laboratory showed less dorsolateral prefrontal cortex to friend positive clips. More positive affect when with friends in daily life was associated with less bilateral anterior insula response to friend positive clips, but greater left anterior insula response to stranger positive clips. Findings provide information on the role of lateral prefrontal cortex and anterior insula in enjoyment of friendships during adolescence.

Temptations of friends: adolescents' neural and behavioral responses to best friends predict risky behavior.

Adolescents are notorious for engaging in risky, reward-motivated behavior, and this behavior occurs most often in response to social reward, typically in the form of peer contexts involving intense positive affect. A combination of greater neural and behavioral sensitivity to peer positive affect may characterize adolescents who are especially likely to engage in risky behaviors. To test this hypothesis, we examined 50 adolescents' reciprocal positive affect and neural response to a personally relevant, ecologically valid pleasant stimulus: positive affect expressed by their best friend during a conversation about past and future rewarding mutual experiences. Participants were typically developing community adolescents (age 14-18 years, 48.6% female), and risky behavior was defined as a factor including domains such as substance use, sexual behavior and suicidality. Adolescents who engaged in more real-life risk-taking behavior exhibited either a combination of high reciprocal positive affect behavior and high response in the left ventrolateral prefrontal cortex-a region associated with impulsive sensation-seeking-or the opposite combination. Behavioral and neural sensitivity to peer influence could combine to contribute to pathways from peer influence to risky behavior, with implications for healthy development.

A High-Throughput Screening Triage Workflow to Authenticate a Novel Series of PFKFB3 Inhibitors.

A high-throughput screen (HTS) of human 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) resulted in several series of compounds with the potential for further optimization. Informatics was used to identify active chemotypes with lead-like profiles and remove compounds that commonly occurred as actives in other HTS screens. The activities were confirmed with IC50 measurements from two orthogonal assay technologies, and further analysis of the Hill slopes and comparison of the ratio of IC50 values at 10 times the enzyme concentration were used to identify artifact compounds. Several series of compounds were rejected as they had both high slopes and poor ratios. A small number of compounds representing the different leading series were assessed using isothermal titration calorimetry, and the X-ray crystal structure of the complex with PFKFB3 was solved. The orthogonal assay technology and isothermal calorimetry were demonstrated to be unreliable in identifying false-positive compounds in this case. Presented here is the discovery of the dihydropyrrolopyrimidinone series of compounds as active and novel inhibitors of PFKFB3, shown by X-ray crystallography to bind to the adenosine triphosphate site. The crystal structures of this series also reveal it is possible to flip the binding mode of the compounds, and the alternative orientation can be driven by a sigma-hole interaction between an aromatic chlorine atom and a backbone carbonyl oxygen. These novel inhibitors will enable studies to explore the role of PFKFB3 in driving the glycolytic phenotype of tumors.

Heightened activity in social reward networks is associated with adolescents' risky sexual behaviors.

Adolescent sexual risk behavior can lead to serious health consequences, yet few investigations have addressed its neurodevelopmental mechanisms. Social neurocircuitry is postulated to underlie the development of risky sexual behavior, and response to social reward may be especially relevant. Typically developing adolescents (N=47; 18M, 29F; 16.3±1.4years; 42.5% sexual intercourse experience) completed a social reward fMRI task and reported their sexual risk behaviors (e.g., lifetime sexual partners) on the Youth Risk Behavior Survey (YRBS). Neural response and functional connectivity to social reward were compared for adolescents with higher- and lower-risk sexual behavior. Adolescents with higher-risk sexual behaviors demonstrated increased activation in the right precuneus and the right temporoparietal junction during receipt of social reward. Adolescents with higher-risk sexual behaviors also demonstrated greater functional connectivity between the precuneus and the temporoparietal junction bilaterally, dorsal medial prefrontal cortex, and left anterior insula/ventrolateral prefrontal cortex. The greater activation and functional connectivity in self-referential, social reward, and affective processing regions among higher sexual risk adolescents underscores the importance of social influence underlying sexual risk behaviors. Furthermore, results suggest an orientation towards and sensitivity to social rewards among youth engaging in higher-risk sexual behavior, perhaps as a consequence of or vulnerability to such behavior.

Neural correlates of autobiographical problem-solving deficits associated with rumination in depression.

BACKGROUND: Analytical rumination can be characterized as negative thoughts focused on searching for answers to personal problems. Failure to think concretely during autobiographical problem-solving (APS) is hypothesized to drive the inability of ruminators to generate effective solutions. Clarifying the brain correlates underlying APS deficits in depressed ruminators may identify novel biological targets for treatment. METHOD: Forty participants (22 unmedicated depressed and 18 never-depressed adults) ranging in rumination engaged in APS and negative self-referential processing (NSP) of negative trait adjectives during fMRI. We contrasted activation during APS with activation during NSP to isolate regions contributing to APS. RESULTS: Rumination was associated with having generated fewer solutions during APS and with a failure to recruit the angular gyrus (AG) and the medial frontal gyrus (MFG) during APS. Rumination was associated with greater MFG activation during NSP and stronger connectivity between the AG and the rostrolateral prefrontal cortex (RLPFC) during APS relative to NSP. Findings were not driven by clinical status. LIMITATIONS: The use of an extreme groups approach can result in overestimation of effects sizes. CONCLUSIONS: Ruminators fail to recruit regions with the default network (DN) that support APS. In particular, a failure to recruit the AG during APS may drive the abstract thinking style previously shown to explain depressed ruminator's difficulty generating concrete solutions. Targeting this mechanism directly may reduce rumination.