Feeling left out: depressed adolescents may atypically recruit emotional salience and regulation networks during social exclusion

Depression is associated with negative attention and attribution biases and maladaptive emotion responsivity and regulation, which adversely impact self‐evaluations and interpersonal relationships. Using functional magnetic resonance imaging, we investigated the neural substrates of these impairments. We compared neural activity recruited by 126 clinically depressed and healthy adolescents (ages 11‐17 years) during social exclusion (Exclusion > Inclusion) using Cyberball. Results revealed significant interaction effects within left anterior insula (AI)/inferior frontal gyrus and left middle temporal gyrus. Insula hyperresponsivity was associated with peer exclusion for depressed adolescents but peer inclusion for healthy adolescents. In additional, healthy adolescents recruited greater lateral temporal activity during peer exclusion. Complementary effect size analyses within independent parcellations offered converging evidence, as well as highlighted medium‐to‐large effects within subgenual/ventral anterior cingulate cortex and lateral prefrontal, lateral temporal and lateral parietal regions implicated in emotion regulation. Depressogenic neural patterns were associated with negative self‐perceptions and negative information processing biases. These findings suggest a neural mechanism underlying cognitive biases in depression, as reflected by emotional hyperresponsivity and maladaptive regulation/reappraisal of negative social evaluative information. This study lends further support for salience and central executive network dysfunction underlying social threat processing, and in particular, highlights the anterior insula as a key region of disturbance in adolescent depression.

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title: Characteristics, correlates, and outcomes of childhood and adolescent depressive disorders
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title: Biased processing of emotional information in girls at risk for depression.
abstract: Researchers have documented that children of depressed mothers are at elevated risk for developing a depressive disorder themselves. There is currently little understanding, however, of what factors place these children at elevated risk. In the present study, the authors investigated whether never-disordered daughters whose mothers have experienced recurrent episodes of depression during their daughters' lifetime are characterized by biased processing of emotional information. Following a negative mood induction, participants completed an emotional-faces dot-probe task. Daughters at elevated risk for depression, but not control daughters of never-disordered mothers, selectively attended to negative facial expressions. In contrast, only control daughters selectively attended to positive facial expressions. These results provide support for cognitive vulnerability models of depression.

title: Attentional biases for angry faces in unipolar depression
abstract: Past research has demonstrated that depression is associated with dysfunctional processing of emotional information. Recent studies demonstrate that a bias in the attentional processing of negative information may be an important cognitive vulnerability factor underlying the onset and maintenance of depression. However, to date, the nature of this attentional bias is still poorly understood and further exploration of this topic to advance current knowledge of attentional biases in depression seems imperative.  This study examined attentional biases for angry facial expressions presented for 1000 ms in 20 patients with major depressive disorder (MDD) and 20 non-depressed control participants (NC) matched for age and gender using an emotional modification of the Exogenous Cueing task.  Patients with MDD showed maintained attention for angry faces compared with neutral faces. In comparison with non-depressed participants they showed a stronger attentional engagement for angry faces. In contrast, the NC group directed attention away from angry faces, more rapidly disengaging their attention compared with neutral faces.  This pattern of results supports the assumption that MDD is characterized by deficits in the attentional processing of negative, interpersonal information and suggests a ‘protective’ bias in non-depressed individuals. Implications in relation to previous research exploring cognitive and interpersonal functioning in depression are discussed.

title: Cognitive Vulnerability-Stress Theories of Depression: Examining Affective Specificity in the Prediction of Depression Versus Anxiety in Three Prospective Studies
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title: Hopelessness depression: A theory-based subtype of depression.
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title: Cognitive vulnerability-stress models of depression in a self-regulatory and psychobiological context.
abstract: Two developments at the University of Pennsylvania in the late 1960s and early 1970s galvanized this cognitive approach to depression. Coming from a clinical perspective, Aaron Beck (1967), a psychiatrist, had abandoned the psychoanalytic account of depression and had begun to develop a cognitive theory that emphasized the negative "automatic thoughts" that seemed to trigger depressive symptoms among his patients. At the same time, Martin Seligman (1975), an experimental psychologist, had begun to formulate his theory of learned helplessness and depression, based on laboratory research about the deleterious effects of uncontrollable, aversive events. Similar to Beck, Seligman emphasized that maladaptive cognitions such as pervasive expectancies of no control over events could precipitate depressive symptoms. These two cognitive theories ignited a veritable explosion o research on depression. Although it is difficult to reconstruct the forces that fueled cognitive approaches to depression, Dykman and Abramson (1990) listed a few whose impact appears likely. First, th rise of information-processing approaches in general (e.g., Neisser, 1967) and the study o social cognition in particular (e.g., Nisbett & Ross, 1980) provided a basic science foundation for a cognitive approach to depression. Second, basic researchers (e.g., Lazarus, 1966 demonstrated that cognitive processes mediate emotional reactions, with the specific con

title: Cognitive vulnerability to emotional disorders.
abstract: A review of recent research on cognitive processing indicates that biases in attention, memory, and interpretation, as well as repetitive negative thoughts, are common across emotional disorders, although they vary in form according to type of disorder. Current cognitive models emphasize specific forms of biased processing, such as variations in the focus of attention or habitual interpretative styles that contribute to the risk of developing particular disorders. As well as predicting risk of emotional disorders, new studies have provided evidence of a causal relationship between processing bias and vulnerability. Beyond merely demonstrating the existence of biased processing, research is thus beginning to explore the cognitive causes of emotional vulnerability, and their modification.

title: Cognitive vulnerability to depression: an investigation of two hypotheses.
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title: Suicidality and cognitive vulnerability to depression among college students: a prospective study.
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title: Self-rumination, self-reflection, and depression: self-rumination counteracts the adaptive effect of self-reflection.
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title: A Unified Model of Depression
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title: Major depression in the national comorbidity survey-adolescent supplement: prevalence, correlates, and treatment.
abstract: To present the 12-month prevalence of DSM-IV major depressive disorder (MDD) and severe MDD; to examine sociodemographic correlates and comorbidity; and to describe impairment and service use.



Data are from the National Comorbidity Survey-Adolescent Supplement (NCS-A), a nationally representative survey of 10,123 adolescents aged 13 to 18 years that assesses DSM-IV disorders using the Composite International Diagnostic Interview (CIDI) Version 3.0. One parent or surrogate of each participating adolescent was also asked to complete a self-administered questionnaire.



Lifetime and 12-month prevalence of MDD were 11.0% and 7.5%, respectively. The corresponding rates of severe MDD were 3.0% and 2.3%. The prevalence of MDD increased significantly across adolescence, with markedly greater increases among females than among males. Most cases of MDD were associated with psychiatric comorbidity and severe role impairment, and a substantial minority reported suicidality. The prevalence of severe MDD was about one-fourth of that of all MDD cases; estimates of impairment and clinical correlates were of 2- to 5-fold greater magnitude for severe versus mild/moderate depression, with markedly higher rates for suicidal thoughts and behaviors. Treatment in any form was received by the majority of adolescents with 12-month DSM-IV MDD (60.4%), but only a minority received treatment that was disorder-specific or from the mental health sector.



Findings underscore the important public health significance of depression among US adolescents and the urgent need to improve screening and treatment access in this population.

title: Stress, sensitive periods and maturational events in adolescent depression
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title: The Construction of the Self: A Developmental Perspective
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title: The emergence of depression in adolescence: Development of the prefrontal cortex and the representation of reward
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title: Conceptions and perceived influence of peer groups: interviews with preadolescents and adolescents.
abstract: 72 fifth-, eighth-, and eleventh-grade boys and girls were interviewed to investigate developmental changes in perceptions of peer groups and group influence. Results indicated that preadolescents defined groups on the basis of common activities and social behavior and considered group influence to be greatest in these domains. Older adolescents were more likely to describe peer-group influence as global and far reaching, affecting one's appearance, illicit acts, attitudes, and values. Corresponding to increases in peer-group conceptions emphasizing group attitudes/norms and global influence were increases in the extent to which subjects felt that peer-group acceptance or rejection influenced self-evaluation. Developmental changes in the apparent reference-group functions of peer groups for adolescent identity formation are discussed.

title: Cognitive Vulnerability–Stress Model of Depression During Adolescence: Investigating Depressive Symptom Specificity in a Multi-Wave Prospective Study
abstract: Depression commonly co-occurs with anxiety and externalizing problems. Etiological factors from a central cognitive theory of depression, the Hopelessness Theory (Abramson et al.  1989), were examined to evaluate whether a negative inferential style about cause, consequence, and self interacted with stressors over time to predict prospective elevations in depressive symptoms specifically compared with typically co-occurring symptoms. Negative inferential style was assessed at baseline in a sample of early and middle adolescents (N = 350, sixth to tenth graders). Measures of general depressive, anhedonic depressive, anxious arousal, general internalizing, and externalizing symptoms and occurrence of stressors were assessed at four time points over a 5-month period. Results using hierarchical linear modeling show that a negative inferential style interacted with negative events to predict prospective symptoms of general and anhedonic depression specifically but not anxious arousal, general internalizing or externalizing symptoms. Negative events predicted prospective elevations of symptoms of anxious arousal, internalizing, and externalizing problems.

title: Empirical evidence of cognitive vulnerability for depression among children and adolescents: a cognitive science and developmental perspective.
abstract: We summarize and integrate research on cognitive vulnerability to depression among children and adolescents. We first review prospective longitudinal studies of the most researched cognitive vulnerability factors (attributional style, dysfunctional attitudes, and self-perception) and depression among youth. We next review research on information processing biases in youth. We propose that the integration of these two literatures will result in a more adequate test of cognitive vulnerability models. Last, we outline a program of research addressing methodological, statistical, and scientific limitations in the cognitive vulnerability literature.

title: Differential Exposure and Reactivity to Interpersonal Stress Predict Sex Differences in Adolescent Depression
abstract: This study tested the hypothesis that higher rates of depression in adolescent girls are explained by their greater exposure and reactivity to stress in the interpersonal domain in a large sample of 15-year-olds. Findings indicate that adolescent girls experienced higher levels of total and interpersonal episodic stress, whereas boys experienced higher levels of chronic stress (academic and close friendship domains). Higher rates of depression in girls were explained by their greater exposure to total stress, particularly interpersonal episodic stress. Adolescent girls were also more reactive (more likely to become depressed) to both total and interpersonal episodic stress. The findings suggest that girls experience higher levels of episodic stress and are more reactive to these stressors, increasing their likelihood of becoming depressed compared to boys. Results were discussed in terms of girls' greater interpersonal focus and implications for understanding sex differences in depression.

title: Peer victimization during adolescence: concurrent and prospective impact on symptoms of depression and anxiety
abstract: Peer victimization is ubiquitous across schools and cultures, and has the potential for long-lasting effects on the well-being of victims. To date, research has focused on the consequences of peer victimization during childhood but neglected adolescence. Peer relationships and approval become increasingly important during adolescence; thus, peer victimization at this age may have a damaging psychological impact.  Participants were 5030 adolescents aged 11–16 recruited from secondary schools in the UK. Self-report measures of victimization and symptoms of anxiety and depression were administered on three occasions over a 12-month period. Latent growth models examined concurrent and prospective victimization-related elevations in anxiety and depression symptoms above individual-specific growth trajectories.  Peer victimization was associated with a concurrent elevation of 0.64 and 0.56 standard deviations in depression and anxiety scores, respectively. There was an independent delayed effect, with additional elevations in depression and anxiety (0.28 and 0.25 standard deviations) six months later. These concurrent and prospective associations were independent of expected symptom trajectories informed by individual risk factors.  Adolescent peer victimization was associated with immediate and delayed elevations in anxiety and depression. Early intervention aimed at identifying and supporting victimized adolescents may prevent the development of these disorders.

title: Peer Victimization, Cue Interpretation, and Internalizing Symptoms: Preliminary Concurrent and Longitudinal Findings for Children and Adolescents
abstract: This study examined hostile intent and causal, critical self-referent attributions for ambiguous peer cues to examine the hypothesis that these latter interpretations would be uniquely associated with symptoms of depression, social anxiety, and loneliness. Critical self-referent attributions were assessed in 116 kindergarteners (Study 1) and 159 adolescents (Study 2) using a hypothetical vignette procedure, replicating past work on social information processing. In both samples, critical self-referent attributions were concurrently associated with depressive symptoms as reported by teacher (Study 1), peer, and self-report (Study 2). Critical self-referent attributions also were concurrently associated with loneliness and with actual peer experiences, including peer rejection in both studies. Results from both studies support a cognitive vulnerability–stress model, suggesting that the tendency to derive critical self-referent attributions from ambiguous peer experiences is most closely associated with depressive symptoms when accompanied by high levels of peer victimization. Longitudinal findings (Study 2) offers preliminary evidence for this cognitive vulnerability–stress model as a predictor of adolescents' depressive symptoms over a 17-month interval.

title: Depression in early, middle and late adolescence: differential evidence for the cognitive diathesis-stress model.
abstract: Cognitive theory is a prominent framework to study depression in both adults and adolescents. This theory stated that dysfunctional schemas are moderators (known as diathesis) in the association of current stress and psychopathology. However, in adolescents, less evidence has been found so far to corroborate the importance of these schemas. This study aimed to investigate in a cross-sectional design the moderating role of adolescents' early maladaptive schemas (EMS) on depressive symptoms. This will be studied in relation to both important daily stressors (i.e., maternal, paternal and peer rejection) and stressful life events.



Adolescents (N = 228, age 12-18 years), selected from inpatient and outpatient clinical settings and a non-referred sample, completed questionnaires and interviews measuring psychopathology, cognitive schemas, peer rejection, maternal and paternal rejection, and stressful life events. Parents completed questionnaires about their adolescent measuring psychopathology, stressful life events and peer rejection, as well as their own parental behaviour.



Correlational analyses revealed significant associations between the study variables. Evidence was found for an interaction effect between the adolescents' EMS and peer rejection in explaining depressive symptoms, but only in late adolescents.



Stress induced by maternal and, in lesser extent, paternal rejection is contributing to depressive symptoms primarily in younger and to lesser extent in older age groups. The quality of peer relationships becomes an increasingly salient source of distress as adolescence unfolds and is certainly an important mechanism affecting depression in adolescence. Maladaptive schemas only start functioning as a cognitive diathesis in late adolescence, increasing depression in response to peer-related distress. Since maladaptive schemas are not yet operating as cognitive vulnerability factors in early and middle adolescence, early interventions for depressive disorders may be more effective compared with treatment in later adolescence.

title: Adolescent social cognitive and affective neuroscience: past, present, and future.
abstract: In this article, we review three areas of research within adolescent social cognitive and affective neuroscience: (i) emotion reactivity and regulation, (ii) mentalizing and (iii) peer relations, including social rejection or acceptance as well as peer influence. The review provides a context for current contributions to the special issue of Social Cognitive and Affective Neuroscience on Adolescence, and highlights three important themes that emerge from the special issue, which are relevant to future research. First, the age of participants studied (and labels for these age groups) is a critical design consideration. We suggest that it might be logical to reduce the reliance on convenience samples of undergraduates to represent adults in psychology and cognitive neuroscience studies, since there is substantial evidence that the brain is still developing within this age range. Second, developmental researchers are broadening their scope of inquiry by testing for non-linear effects, via increased use of longitudinal strategies or much wider age ranges and larger samples. Third, there is increasing appreciation for the interrelatedness of the three areas of focus in this special issue (emotion reactivity and regulation, mentalizing, and peer relations), as well as with other areas of interest in adolescent development.

title: Cognitive Moderators of the Longitudinal Association Between Peer Rejection and Adolescent Depressive Symptoms
abstract: This longitudinal study examined peer rejection as a predictor of adolescent depressive symptoms during the critical developmental period associated with substantial increases in the prevalence of girls' depression. In a sample of 158 adolescents aged 15–17 years, a peer nomination, sociometric assessment was conducted to examine adolescents' peer status at an initial time point, along with self-report measures of depressive symptoms, depressogenic attributions, and peer importance. Adolescents completed a second measure of depressive symptoms 17 months later. Results were consistent with integrated cognitive vulnerability-stress and cognitive dissonance models, particularly for girls. Specifically, peer rejection was a significant prospective predictor of depressive symptoms when combined with high levels of importance ascribed to peer status and high levels of adolescents' depressogenic attributional styles.

title: Stress response and the adolescent transition: Performance versus peer rejection stressors
abstract: Little is known about normative variation in stress response over the adolescent transition. This study examined neuroendocrine and cardiovascular responses to performance and peer rejection stressors over the adolescent transition in a normative sample. Participants were 82 healthy children (ages 7–12 years, n = 39, 22 females) and adolescents (ages 13–17, n = 43, 20 females) recruited through community postings. Following a habituation session, participants completed a performance (public speaking, mental arithmetic, mirror tracing) or peer rejection (exclusion challenges) stress session. Salivary cortisol, salivary alpha amylase (sAA), systolic and diastolic blood pressure (SBP, DBP), and heart rate were measured throughout. Adolescents showed significantly greater cortisol, sAA, SBP, and DBP stress response relative to children. Developmental differences were most pronounced in the performance stress session for cortisol and DBP and in the peer rejection session for sAA and SBP. Heightened physiological stress responses in typical adolescents may facilitate adaptation to new challenges of adolescence and adulthood. In high-risk adolescents, this normative shift may tip the balance toward stress response dysregulation associated with depression and other psychopathology. Specificity of physiological response by stressor type highlights the importance of a multisystem approach to the psychobiology of stress and may also have implications for understanding trajectories to psychopathology.

title: Increased neural response to peer rejection associated with adolescent depression and pubertal development.
abstract: Sensitivity to social evaluation has been proposed as a potential marker or risk factor for depression, and has also been theorized to increase with pubertal maturation. This study utilized an ecologically valid paradigm to test the hypothesis that adolescents with major depressive disorder (MDD) would show altered reactivity to peer rejection and acceptance relative to healthy controls in a network of ventral brain regions implicated in affective processing of social information. A total of 48 adolescents (ages 11-17), including 21 with a current diagnosis of MDD and 27 age- and gender-matched controls, received rigged acceptance and rejection feedback from fictitious peers during a simulated online peer interaction during functional neuroimaging. MDD youth showed increased activation to rejection relative to controls in the bilateral amygdala, subgenual anterior cingulate, left anterior insula and left nucleus accumbens. MDD and healthy youth did not differ in response to acceptance. Youth more advanced in pubertal maturation also showed increased reactivity to rejection in the bilateral amygdala/parahippocampal gyrus and the caudate/subgenual anterior cingulate, and these effects remained significant when controlling for chronological age. Findings suggest that increased reactivity to peer rejection is a normative developmental process associated with pubertal development, but is particularly enhanced among youth with depression.

title: Depression from childhood through adolescence: Risk mechanisms across multiple systems and levels of analysis.
abstract: This paper selectively reviews recent research, especially in the last two years (2012-2014) in preschool, child, and adolescent depression. In particular, attention is paid to developmental epidemiology as well as risk factors and processes that contribute to depression trajectories over time. Emphasis is placed on a developmental psychopathology perspective in which risks are instantiated across multiple systems and levels of analysis, including genetics, stress contexts and processes, biological stress mechanisms, temperament, emotion, reward, cognitive factors and processes, and interpersonal influences. These risks dynamically transact over time, as they emerge and stabilize into relatively trait-like vulnerabilities that confer risk for the increasing rates of depression observed in adolescence. Overall, this summary illustrates that considerable progress has been made recently in understanding the complex developmental processes contributing to depression. Finally, a few gaps are highlighted as opportunities for future research.

title: The neurobiology of the emotional adolescent: From the inside out
abstract: Adolescents are commonly portrayed as highly emotional, with their behaviors often hijacked by their emotions. Research on the neural substrates of adolescent affective behavior is beginning to paint a more nuanced picture of how neurodevelopmental changes in brain function influence affective behavior, and how these influences are modulated by external factors in the environment. Recent neurodevelopmental models suggest that the brain is designed to promote emotion regulation, learning, and affiliation across development, and that affective behavior reciprocally interacts with age-specific social demands and different social contexts. In this review, we discuss current findings on neurobiological mechanisms of adolescents' affective behavior and highlight individual differences in and social-contextual influences on adolescents' emotionality. Neurobiological mechanisms of affective processes related to anxiety and depression are also discussed as examples. As the field progresses, it will be critical to test new hypotheses generated from the foundational empirical and conceptual work and to focus on identifying more precisely how and when neural networks change in ways that promote or thwart adaptive affective behavior during adolescence.

title: Affect regulation in depressed and nondepressed children and young adolescents
abstract: The present !tudy examined children's reported frequency and efficacy of strategies for regulating their negative affect in respoll.le to a description of a particuJar affwative (fight with a friend) or achievement (loss at a game) !ituation. The 275 children were in kindergarten through cil;hth grade; they completed the Chilw-en's Dep;ession Inventory and either the "Fight" c; ''Game" version of the Child Affect Qucstiono.aire (CAQ-F or CAQ-G). Children who endorsed higher levels of depressive symptom! generally reported using affect regulation strategiC3 significantly less often than did nondepres!ed children, and they ruted these responses a! significantly less effC'Ctive in altering their negative mood. Depressed girls rated mother-initiated affect regulation strategies ao! less effective than did nondepressed girls. Younger children rated both self- and mother-initiated strategies as more effective than did older children. Several directions for future research arc suggested.

title: Emotion regulation in depression: Relation to cognitive inhibition
abstract: Depression is a disorder of impaired emotion regulation. Consequently, examining individual differences in the habitual use of emotion-regulation strategies has considerable potential to inform models of this debilitating disorder. The aim of the current study was to identify cognitive processes that may be associated with the use of emotion-regulation strategies and to elucidate their relation to depression. Depression has been found to be associated with difficulties in cognitive control and, more specifically, with difficulties inhibiting the processing of negative material. We used a negative affective priming task to assess the relations among inhibition and individual differences in the habitual use of rumination, reappraisal, and expressive suppression in clinically depressed, formerly depressed, and never-depressed participants. We found that depressed participants exhibited the predicted lack of inhibition when processing negative material. Moreover, within the group of depressed participants, reduced inhibition of negative material was associated with greater rumination. Across the entire sample, reduced inhibition of negative material was related to less use of reappraisal and more use of expressive suppression. Finally, within the formerly depressed group, less use of reappraisal, more use of rumination, and greater expressive suppression were related to higher levels of depressive symptoms. These findings suggest that individual differences in the use of emotion-regulation strategies play an important role in depression, and that deficits in cognitive control are related to the use of maladaptive emotion-regulation strategies in this disorder.

title: Neurocognitive bases of emotion regulation development in adolescence
abstract: Highlights • Adolescence is a period of increased emotional reactivity and psychopathology.• Adolescent emotion regulation (ER) is discussed in relation to the developing brain.• Implicit emotion regulation develops non-linearly, mirroring brain development.• Explicit ER findings are mixed due to limited studies and differing methods.• Development of adaptive ER strategies can support interventions for psychopathology.

title: Selective attention biases of people with depression: Positive and negative priming of depression-related information
abstract: Selective attention biases are believed to be one of the cognitive vulnerabilities to depression. This study examined two types of attention biases, namely attention facilitation and attention disinhibition, towards mood-congruent words in 40 clinically depressed outpatients and 40 never-depressed healthy controls. Measures were differential reaction time towards neutral and depressive words in the positive and negative priming paradigms that were used to assess attention facilitation and attention disinhibition, respectively. Results showed that the depressed group exhibited enhanced attention facilitation to depressive words relative to neutral words, whereas the control group did not. The differential reduction of reaction time of the depressed group to the previously presented depressive words relative to the previously presented neutral words was greater than that in the control group. On the other hand, both groups showed similar attention disinhibition to depressive words relative to neutral words. The differential increase in reaction time to previously ignored depressive words relative to the previously ignored neutral words was similar in both groups. The above results suggest that major depressive disorder is characterized by attention facilitation by mood-congruent information, but inhibition difficulties in attention to depression-related information is not specific to depressive disorder.

title: Brain Activation During Emotional Memory Processing Associated with Subsequent Course of Depression
abstract: Major depressive disorder (MDD) is characterized by a heterogeneous course and identifying patients at risk for an unfavorable course is difficult. Neuroimaging studies may identify brain predictors of clinical course and may help to further unravel the neurobiological processes underlying an unfavorable course. We investigated whether brain activation during an emotional memory paradigm is associated with depressive course. To this end, we followed 74 MDD patients and 45 healthy controls (HCs) for 2 years. At baseline, participants performed an emotional word-encoding and -recognition task during functional magnetic resonance imaging. Activation patterns were compared between patients with fast remission (n=22), remission with recurrence (n=23), non-remission (n=29), and HCs. Additionally, linear relations of brain activation and time to remission during the follow-up period were investigated across patients. We observed that during encoding of negative words, non-remitters showed higher activation of the left insula than HCs. Groups also differed in activation of the right hippocampus and left amygdala during negative encoding, with a trend for higher activation in non-remitters compared with HCs. Furthermore, hippocampal activation during negative word encoding was significantly and positively correlated with time to remission, irrespective of illness severity. Our findings suggest that higher activation in the left insula could serve as a neural marker of a naturalistic non-remitting course, whereas higher hippocampal activation is associated with delayed remission. Longitudinal analyses should clarify whether abnormal activation progresses further as a function of time with depression or may serve as load-independent markers of MDD course.

title: Association between individual differences in self-reported emotional resilience and the affective perception of neutral faces.
abstract: Resilience, i.e., the ability to cope with stress and adversity, relies heavily on judging adaptively complex situations. Judging facial emotions is a complex process of daily living that is important for evaluating the affective context of uncertain situations, which could be related to the individual's level of resilience. We used a novel experimental paradigm to test the hypothesis that highly resilient individuals show a judgment bias towards positive emotions.



65 non-treatment seeking subjects completed a forced emotional choice task when presented with neutral faces and faces morphed to display a range of emotional intensities across sadness, fear, and happiness.



Overall, neutral faces were judged more often to be sad or fearful than happy. Furthermore, high compared to low resilient individuals showed a bias towards happiness, particularly when judging neutral faces.



This is a cross-sectional study with a non-clinical sample.



These results support the hypothesis that resilient individuals show a bias towards positive emotions when faced with uncertain emotional expressions. This capacity may contribute to their ability to better cope with certain types of difficult situations, especially those that are interpersonal in nature.

title: Dynamics of affective experience and behavior in depressed adolescents.
abstract: Depression is often characterized as a disorder of affect regulation. However, research focused on delineating the key dimensions of affective experience (other than valence) that are abnormal in depressive disorder has been scarce, especially in child and adolescent samples. As definitions of affect regulation center around processes involved in initiating, maintaining, and modulating the occurrence, intensity, and duration of affective experiences, it is important to examine the extent to which affective experiences of depressed youth differ on these dimensions from those of healthy youth.



The affective behavior and experience of adolescents with major depressive disorder (MDD; n = 75) were compared to a demographically matched cohort of healthy adolescents (n = 77). Both samples were recruited from community high schools. A multi-source (parents and adolescent), multi-method (interviews, behavioral observations, questionnaires) assessment strategy was used to examine positive and negative affects.



Depressed youth had significantly longer durations, higher frequency, and greater intensity when experiencing angry and dysphoric affects and shorter durations and less frequency of happy affect when compared to healthy youth. The most consistent, cross-method results were evident for duration of affect.



Clinically depressed adolescents experienced disturbances in affective functioning that were evident in the occurrence, intensity, and duration of affect. Notably, the disturbances were apparent in both positive and negative affects.

title: Dysfunction in the neural circuitry of emotional self-regulation in major depressive disorder
abstract: An inability to self-regulate negative emotions appears to play a pivotal role in the genesis of major depressive disorder. This inability may be related to a dysfunction of the neural circuitry underlying emotional self-regulation. This functional magnetic resonance imaging study was conducted to test this hypothesis. Depressed individuals and controls were scanned while they attempted to voluntarily down-regulate sad feelings. The degree of difficulty experienced during down-regulation of sadness was higher in depressed individuals. Furthermore, there was greater activation in the right dorsal anterior cingulate cortex, right anterior temporal pole, right amygdala, and right insula in depressed individuals. These results suggest that emotional dysregulation in major depressive disorder is related to a disturbance in the neural circuitry of emotional self-regulation.

title: Functional brain imaging studies of youth depression: A systematic review☆
abstract: There is growing interest in understanding the neurobiology of major depressive disorder (MDD) in youth, particularly in the context of neuroimaging studies. This systematic review provides a timely comprehensive account of the available functional magnetic resonance imaging (fMRI) literature in youth MDD.  A literature search was conducted using PubMED, PsycINFO and Science Direct databases, to identify fMRI studies in younger and older youth with MDD, spanning 13–18 and 19–25 years of age, respectively.  Twenty-eight studies focusing on 5 functional imaging domains were identified, namely emotion processing, cognitive control, affective cognition, reward processing and resting-state functional connectivity. Elevated activity in “extended medial network” regions including the anterior cingulate, ventromedial and orbitofrontal cortices, as well as the amygdala was most consistently implicated across these five domains. For the most part, findings in younger adolescents did not differ from those in older youth; however a general comparison of findings in both groups compared to adults indicated differences in the domains of cognitive control and affective cognition.  Youth MDD is characterized by abnormal activations in ventromedial frontal regions, the anterior cingulate and amygdala, which are broadly consistent with the implicated role of medial network regions in the pathophysiology of depression. Future longitudinal studies examining the effects of neurodevelopmental changes and pubertal maturation on brain systems implicated in youth MDD will provide a more comprehensive neurobiological model of youth depression.

title: Neural mechanisms of the cognitive model of depression
abstract: In the 40 years since Aaron Beck first proposed his cognitive model of depression, the elements of this model — biased attention, biased processing, biased thoughts and rumination, biased memory, and dysfunctional attitudes and schemas — have been consistently linked with the onset and maintenance of depression. Although numerous studies have examined the neural mechanisms that underlie the cognitive aspects of depression, their findings have not been integrated with Beck's cognitive model. In this Review, we identify the functional and structural neurobiological architecture of Beck's cognitive model of depression. Although the mechanisms underlying each element of the model differ, in general the negative cognitive biases in depression are facilitated by increased influence from subcortical emotion processing regions combined with attenuated top-down cognitive control.

title: Major Depressive Disorder and Alterations in Insular Cortical Activity: A Review of Current Functional Magnetic Imaging Research
abstract: Major depressive disorder (MDD) is characterized by a dysregulated fronto-limbic network. The hyperactivation of limbic regions leads to increased attention and processing of emotional information, with a bias toward negative stimuli. Pathological ruminative behavior is a common symptom of depressive disorder whereby the individual is unable to disengage from internal mental processing of emotionally salient events. In fact, lower deactivations of the neural baseline resting state may account for the increased internal self-focus. The insular cortex, with its extensive connections to fronto-limbic and association areas has recently also been implicated to be a part of this network. Given its wide-reaching connectivity, it has been putatively implicated as an integration center of autonomic, visceromotor, emotional, and interoceptive information. The following paper will review recent imaging findings of altered insular function and connectivity in depressive pathology.

title: Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders
abstract: Neuroimaging technology has provided unprecedented opportunities for elucidating the anatomical correlates of major depression. The knowledge gained from imaging research and from the postmortem studies that have been guided by imaging data is catalyzing a paradigm shift in which primary mood disorders are conceptualized as illnesses that involve abnormalities of brain structure, as well as of brain function. These data suggest specific hypotheses regarding the neural mechanisms underlying pathological emotional processing in mood disorders. They particularly support a role for dysfunction within the prefrontal cortical and striatal systems that normally modulate limbic and brainstem structures involved in mediating emotional behavior in the pathogenesis of depressive symptoms.

title: A meta‐analytic study of changes in brain activation in depression
abstract: A large number of studies with considerably variable methods have been performed to investigate brain regions involved in the pathophysiology of major depressive disorder. The aim of this study was to use a quantitative meta‐analytic technique to synthesise the results of much of this research.  Three separate quantitative meta‐analytical studies were conducted using the Activation Likelihood Estimation technique. Analysis was performed on three types of studies: (1) those conducted at rest comparing brain activation in patients with depression and controls; (2) those involving brain changes following antidepressant treatment; and (3) those comparing brain activation patterns induced by the induction of positive or negative emotion in patients with depression compared with controls.  There appears to be a complex series of areas of the brain implicated in the pathophysiology of depression although limited overlap was found across imaging paradigms. This included a network of regions including frontal and temporal cortex as well as the insula and cerebellum that are hypoactive in depressed subjects and in which there is increase in activity with treatment. There was a corresponding set of subcortical and limbic regions in which opposite changes were found.  There is limited overlap between the brain regions identified using differing imaging methods. The most consistently identified regions include areas of the anterior cingulate, dorsolateral, medial and inferior prefrontal cortex, insula, superior temporal gyrus, basal ganglia and cerebellum. Further research is required to identify if different imaging methods are identifying complementary networks that are equally involved in the disorder.

title: Predictive neural biomarkers of clinical response in depression: A meta-analysis of functional and structural neuroimaging studies of pharmacological and psychological therapies
abstract: We performed a systematic review and meta-analysis of neural predictors of response to the most commonly used, evidence based treatments in clinical practice, namely pharmacological and psychological therapies. Investigations of medication-free subjects suffering from a current major depressive episode who underwent positron emission tomography (PET) or functional or structural magnetic resonance imaging (MRI) scans prior to the initiation of treatment were reviewed. Results of 20 studies from 15 independent samples were included in the functional imaging meta-analysis and 9 studies from 6 independent samples in the structural neuroimaging meta-analysis. Regional activations with prognostic value include the well replicated finding that increased baseline activity in the anterior cingulate is predictive of a higher likelihood of improvement. As well, increased baseline activation in the insula and striatum is associated with higher likelihood of a poorer clinical response. Structural neuroimaging studies indicated that a decrease in right hippocampal volume is a statistically significant predictor of poorer treatment response. Overall, the predictive information that is measurable with brain imaging techniques is both multimodal and regionally distributed as it contains functional as well as structural correlates which encompass several brain regions within a frontostriatal-limbic network. To develop clinically relevant, prognostic markers will require high predictive accuracy at the level of the individual. Predicting clinical response will help to stratify patients and to identify at an early stage those patients who may require more intensive or combined therapies. We propose that structural and functional neuroimaging show significant potential for the development of prognostic markers of clinical response in the treatment of depression.

title: A Meta-Analysis of Changes in Brain Activity in Clinical Depression
abstract: Insights into neurobiological mechanisms of depression are increasingly being sought via brain imaging studies. Our aim was to quantitatively summarize overlap and divergence in regions of altered brain activation associated with depression under emotionally valenced compared to cognitively demanding task conditions, and with reference to intrinsic functional connectivity. We hypothesized differences reflective of task demands. A co-ordinate-based meta-analysis technique, activation likelihood estimation, was used to analyze relevant imaging literature. These studies compared brain activity in depressed adults relative to healthy controls during three conditions: (i) emotionally valenced (cognitively easy) tasks (n = 29); (ii) cognitively demanding tasks (n = 15); and (iii) resting conditions (n = 21). The meta-analyses identified five, eight, and seven significant clusters of altered brain activity under emotion, cognition, and resting conditions, respectively, in depressed individuals compared to healthy controls. Regions of overlap and divergence between pairs of the three separate meta-analyses were quantified. There were no significant regions of overlap between emotion and cognition meta-analyses, but several divergent clusters were found. Cognitively demanding conditions were associated with greater activation of right medial frontal and insula regions while bilateral amygdala was more significantly altered during emotion (cognitively undemanding) conditions; consistent with task demands. Overlap was present in left amygdala and right subcallosal cingulate between emotion and resting meta-analyses, with no significant divergence. Our meta-analyses highlight alteration of common brain regions, during cognitively undemanding emotional tasks and resting conditions but divergence of regions between emotional and cognitively demanding tasks. Regions altered reflect current biological and system-level models of depression and highlight the relationship with task condition and difficulty.

title: Neuroimaging-based biomarkers for treatment selection in major depressive disorder
abstract: The use of neuroimaging approaches to identify likely treatment outcomes in patients with major depressive disorder is developing rapidly. Emerging work suggests that resting state pretreatment metabolic activity in the fronto-insular cortex may distinguish between patients likely to respond to psychotherapy or medication and may function as a treatment-selection biomarker. In contrast, high metabolic activity in the subgenual anterior cingulate cortex may be predictive of poor outcomes to both medication and psychotherapy, suggesting that nonstandard treatments may be pursued earlier in the treatment course. Although these findings will require replication before clinical adoption, they provide preliminary support for the concept that brain states can be measured and applied to the selection of a specific treatment most likely to be beneficial for an individual patient.

title: A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks
abstract: Cognitively demanding tasks that evoke activation in the brain's central-executive network (CEN) have been consistently shown to evoke decreased activation (deactivation) in the default-mode network (DMN). The neural mechanisms underlying this switch between activation and deactivation of large-scale brain networks remain completely unknown. Here, we use functional magnetic resonance imaging (fMRI) to investigate the mechanisms underlying switching of brain networks in three different experiments. We first examined this switching process in an auditory event segmentation task. We observed significant activation of the CEN and deactivation of the DMN, along with activation of a third network comprising the right fronto-insular cortex (rFIC) and anterior cingulate cortex (ACC), when participants perceived salient auditory event boundaries. Using chronometric techniques and Granger causality analysis, we show that the rFIC-ACC network, and the rFIC, in particular, plays a critical and causal role in switching between the CEN and the DMN. We replicated this causal connectivity pattern in two additional experiments: (i) a visual attention “oddball” task and (ii) a task-free resting state. These results indicate that the rFIC is likely to play a major role in switching between distinct brain networks across task paradigms and stimulus modalities. Our findings have important implications for a unified view of network mechanisms underlying both exogenous and endogenous cognitive control.

title: Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of base line activation and neural response data.
abstract: Functional neuroimaging investigations of major depressive disorder can advance both the neural theory and treatment of this debilitating illness. Inconsistency of neuroimaging findings and the use of region-of-interest approaches have hindered the development of a comprehensive, empirically informed neural model of major depression. In this context, the authors sought to identify reliable anomalies in baseline neural activity and neural response to affective stimuli in major depressive disorder.



The authors applied voxel-wise, whole-brain meta-analysis to neuroimaging investigations comparing depressed to healthy comparison groups with respect to baseline neural activity or neural response to positively and/or negatively valenced stimuli.



Relative to healthy subjects, those with major depression had reliably higher baseline activity, bilaterally, in the pulvinar nucleus. The analysis of neural response studies using negative stimuli showed greater response in the amygdala, insula, and dorsal anterior cingulate cortex and lower response in the dorsal striatum and dorsolateral prefrontal cortex in individuals with major depressive disorder than in healthy subjects.



The meta-analytic results support an elegant and neuroanatomically viable model of the salience of negative information in major depressive disorder. In this proposed model, high baseline pulvinar activity in depression first potentiates responding of the brain's salience network to negative information; next, and owing potentially to low striatal dopamine levels in depression, this viscerally charged information fails to propagate up the cortical-striatal-pallidalthalamic circuit to the dorsolateral prefrontal cortex for contextual processing and reappraisal.

title: Saliency, switching, attention and control: a network model of insula function
abstract: The insula is a brain structure implicated in disparate cognitive, affective, and regulatory functions, including interoceptive awareness, emotional responses, and empathic processes. While classically considered a limbic region, recent evidence from network analysis suggests a critical role for the insula, particularly the anterior division, in high-level cognitive control and attentional processes. The crucial insight and view we present here is of the anterior insula as an integral hub in mediating dynamic interactions between other large-scale brain networks involved in externally oriented attention and internally oriented or self-related cognition. The model we present postulates that the insula is sensitive to salient events, and that its core function is to mark such events for additional processing and initiate appropriate control signals. The anterior insula and the anterior cingulate cortex form a “salience network” that functions to segregate the most relevant among internal and extrapersonal stimuli in order to guide behavior. Within the framework of our network model, the disparate functions ascribed to the insula can be conceptualized by a few basic mechanisms: (1) bottom–up detection of salient events, (2) switching between other large-scale networks to facilitate access to attention and working memory resources when a salient event is detected, (3) interaction of the anterior and posterior insula to modulate autonomic reactivity to salient stimuli, and (4) strong functional coupling with the anterior cingulate cortex that facilitates rapid access to the motor system. In this manner, with the insula as its integral hub, the salience network assists target brain regions in the generation of appropriate behavioral responses to salient stimuli. We suggest that this framework provides a parsimonious account of insula function in neurotypical adults, and may provide novel insights into the neural basis of disorders of affective and social cognition.

title: Facial emotion processing in major depression: a systematic review of neuroimaging findings
abstract: BackgroundCognitive models of depression suggest that major depression is characterized by biased facial emotion processing, making facial stimuli particularly valuable for neuroimaging research on the neurobiological correlates of depression. The present review provides an overview of functional neuroimaging studies on abnormal facial emotion processing in major depression. Our main objective was to describe neurobiological differences between depressed patients with major depressive disorder (MDD) and healthy controls (HCs) regarding brain responsiveness to facial expressions and, furthermore, to delineate altered neural activation patterns associated with mood-congruent processing bias and to integrate these data with recent functional connectivity results. We further discuss methodological aspects potentially explaining the heterogeneity of results. Medline search was performed up to August 2011 in order to identify studies on emotional face processing in acutely depressed patients compared with HCs. A total of 25 studies using functional magnetic resonance imaging were reviewed.ResultsThe analysis of neural activation data showed abnormalities in MDD patients in a common face processing network, pointing to mood-congruent processing bias (hyperactivation to negative and hypoactivation to positive stimuli) particularly in the amygdala, insula, parahippocampal gyrus, fusiform face area, and putamen. Furthermore, abnormal activation patterns were repeatedly found in parts of the cingulate gyrus and the orbitofrontal cortex, which are extended by investigations implementing functional connectivity analysis. However, despite several converging findings, some inconsistencies are observed, particularly in prefrontal areas, probably caused by heterogeneities in paradigms and patient samples.ConclusionsFurther studies in remitted patients and high-risk samples are required to discern whether the described abnormalities represent state or trait characteristics of depression.

title: Functional connectivity of negative emotional processing in adolescent depression.
abstract: The subgenual anterior cingulate cortex (sgACC) and its connected circuitry have been heavily implicated in emotional functioning in adolescent-onset major depressive disorder (MDD). While several recent studies have examined sgACC functional connectivity (FC) in depressed youth at rest, no studies to date have investigated sgACC FC in adolescent depression during negative emotional processing.



Nineteen medication-naïve adolescents with MDD and 19 matched healthy controls (HCL) performed an implicit fear facial affect recognition task during functional magnetic resonance imaging (fMRI). We defined seeds in bilateral sgACC and assessed FC using the psychophysiological interaction method. We also applied cognitive behavioral modeling to estimate group differences in perceptual sensitivity in this task. Finally, we correlated connectivity strength with clinical data and perceptual sensitivity.



Depressed adolescents showed increased sgACC-amygdala FC and decreased sgACC-fusiform gyrus, sgACC-precuneus, sgACC-insula, and sgACC-middle frontal gyrus FC compared to HCL (p<0.05, corrected). Among the MDD, sgACC-precuneus FC negatively correlated with depression severity (p<0.05, corrected). Lastly, MDD adolescents exhibited poorer perceptual sensitivity in the task than HCL, and individual differences in perceptual sensitivity significantly correlated with sgACC FC and depression scores (p<0.05, corrected).



Subjects were clinically homogenous, possibly limiting generalizability of the findings.



Adolescent depression is associated with biased processing of negative stimuli that may be driven by sgACC dysregulation and may possibly lead to an imbalance among intrinsic functional brain networks. This work also establishes the use of combining neuroimaging and cognitive behavioral modeling methods to investigate cognitive and neural differences between psychiatric and healthy populations.

title: Altered insular activation and increased insular functional connectivity during sad and happy face processing in adolescent major depressive disorder.
abstract: Major depressive disorder (MDD) is a leading cause of disability worldwide and occurs commonly first during adolescence. The insular cortex (IC) plays an important role in integrating emotion processing with interoception and has been implicated recently in the pathophysiology of adult and adolescent MDD. However, no studies have yet specifically examined the IC in adolescent MDD during processing of faces in the sad-happy continuum. Thus, the aim of the present study is to investigate the IC during sad and happy face processing in adolescents with MDD compared to healthy controls (HCL).



Thirty-one adolescents (22 female) with MDD and 36 (23 female) HCL underwent a well-validated emotional processing fMRI paradigm that included sad and happy face stimuli.



The MDD group showed significantly less differential activation of the anterior/middle insular cortex (AMIC) in response to sad versus happy faces compared to the HCL group. AMIC also showed greater functional connectivity with right fusiform gyrus, left middle frontal gyrus, and right amygdala/parahippocampal gyrus in the MDD compared to HCL group. Moreover, differential activation to sad and happy faces in AMIC correlated negatively with depression severity within the MDD group.



Small age-range and cross-sectional nature precluded assessment of development of the AMIC in adolescent depression.



Given the role of the IC in integrating bodily stimuli with conscious cognitive and emotional processes, our findings of aberrant AMIC function in adolescent MDD provide a neuroscientific rationale for targeting the AMIC in the development of new treatment modalities.

title: Failure to Regulate: Counterproductive Recruitment of Top-Down Prefrontal-Subcortical Circuitry in Major Depression
abstract: Although depressed mood is a normal occurrence in response to adversity in all individuals, what distinguishes those who are vulnerable to major depressive disorder (MDD) is their inability to effectively regulate negative mood when it arises. Investigating the neural underpinnings of adaptive emotion regulation and the extent to which such processes are compromised in MDD may be helpful in understanding the pathophysiology of depression. We report results from a functional magnetic resonance imaging study demonstrating left-lateralized activation in the prefrontal cortex (PFC) when downregulating negative affect in nondepressed individuals, whereas depressed individuals showed bilateral PFC activation. Furthermore, during an effortful affective reappraisal task, nondepressed individuals showed an inverse relationship between activation in left ventrolateral PFC and the amygdala that is mediated by the ventromedial PFC (VMPFC). No such relationship was found for depressed individuals, who instead show a positive association between VMPFC and amygdala. Pupil dilation data suggest that those depressed patients who expend more effort to reappraise negative stimuli are characterized by accentuated activation in the amygdala, insula, and thalamus, whereas nondepressed individuals exhibit the opposite pattern. These findings indicate that a key feature underlying the pathophysiology of major depression is the counterproductive engagement of right prefrontal cortex and the lack of engagement of left lateral-ventromedial prefrontal circuitry important for the downregulation of amygdala responses to negative stimuli.

title: Amygdala response and functional connectivity during emotion regulation: a study of 14 depressed adolescents.
abstract: Ineffective emotion regulation and abnormal amygdala activation have each been found in adolescent-onset major depressive disorder. However, amygdala activation during emotion regulation has not been studied in adolescent-onset major depressive disorder.



Fourteen unmedicated adolescents diagnosed with current depression without comorbid psychiatric disorders and fourteen well-matched controls ages 13 to 17 years underwent an emotional regulation task during functional magnetic resonance imaging. During this task, participants viewed negatively-valence images and were asked to notice how they were feeling without trying to change it and maintain their emotional reaction ("Maintain") or to interpret the image in such a way as minimize their emotional response ("Reduce").



Imaging analyses demonstrated that adolescents with depression showed: (1) greater right amygdala activation during the maintain condition relative to controls, (2) less connectivity during the maintain condition between the amygdala and both the insula and medial prefrontal cortex than controls, and (3) a significant positive correlation between amygdala-seeded connectivities during maintenance of emotion and psychosocial functioning.



The current study is a cross-sectional comparison and longitudinal investigations with larger sample sizes are needed to examine the association between amygdala reactivity and emotion regulation over time in adolescent MDD.



During the maintain condition, adolescents with depression showed a heightened amygdala response and less reciprocal activation in brain regions that may modulate the amygdala. A poorly modulated, overreactive amygdala may contribute to poor emotion regulation.

title: Cognitive reappraisal of peer rejection in depressed versus non-depressed adolescents: functional connectivity differences.
abstract: Depression is the most common psychiatric disorder in adolescence, and is characterised by an inability to down-regulate negative emotional responses to stress. Adult studies suggest this may be associated with reduced functional connectivity between prefrontal and subcortical regions, yet the neurological mechanisms in adolescence remain unclear.



We developed a novel, age-appropriate, reappraisal paradigm to investigate functional connectivity during reappraisal of a real-life source of stress in 15 depressed and 15 non-depressed adolescents. During fMRI, participants i) attended to, and ii) implemented reappraisal techniques (learnt prior to fMRI) in response to, rejection.



Reappraisal reduced negative mood and belief in negative thoughts in both groups alike, however during reappraisal (versus attend) trials, depressed adolescents showed greater connectivity between the right frontal pole and numerous subcortical and cortical regions than non-depressed adolescents.



These findings tentatively suggest that, when instructed, depressed adolescents do have the ability to engage neural networks involved in emotion regulation, possibly because adolescence reflects a period of heightened plasticity. These data support the value of cognitive reappraisal as a treatment tool, identify neural markers that could be used to optimise current therapies, and lay the foundations for developing novel neuroscientific techniques for the treatment of adolescent depression.

title: Subgenual anterior cingulate responses to peer rejection: A marker of adolescents' risk for depression
abstract: Extensive developmental research has linked peer rejection during adolescence with a host of psychopathological outcomes, including depression. Moreover, recent neuroimaging research has suggested that increased activity in the subgenual region of the anterior cingulate cortex (subACC), which has been consistently linked with depression, is related to heightened sensitivity to peer rejection among adolescents. The goal of the current study was to directly test the hypothesis that adolescents' subACC responses are predictive of their risk for future depression, by examining the relationship between subACC activity during peer rejection and increases in depressive symptoms during the following year. During a functional magnetic resonance imaging scan, 20 13-year-olds were ostensibly excluded by peers during an online social interaction. Participants' depressive symptoms were assessed via parental reports at the time of the scan and 1 year later. Region of interest and whole-brain analyses indicated that greater subACC activity during exclusion was associated with increases in parent-reported depressive symptoms during the following year. These findings suggest that subACC responsivity to social exclusion may serve as a neural marker of adolescents' risk for future depression and have implications for understanding the relationship between sensitivity to peer rejection and the increased risk of depression that occurs during adolescence.

title: Adding insult to injury: neural sensitivity to social exclusion is associated with internalizing symptoms in chronically peer-victimized girls.
abstract: Despite evidence documenting activation of the social pain network in response to social rejection and its link to temporary distress, far less is known regarding its role in pervasive emotional difficulties. Moreover, research has not considered the intersection between neural activation to experimentally induced social exclusion and naturally occurring social adversity. This study examined an integrated social pain model of internalizing symptoms, which posits that (i) neural sensitivity in the social pain network is associated with internalizing symptoms, (ii) this linkage is more robust in youth with than without a history of social adversity, and (iii) heightened avoidance motivation serves as one pathway linking neural sensitivity and internalizing symptoms. During a functional magnetic resonance imaging scan, 47 adolescent girls (M age = 15.46 years, SD = .35) with well-characterized histories of peer victimization were exposed to social exclusion. Whole-brain analyses revealed that activation to exclusion in the social pain network was associated with internalizing symptoms. As anticipated, this linkage was stronger in chronically victimized than non-victimized girls and was partially accounted for by avoidance motivation. This research indicates the importance of integrating neural, social and psychological systems of development in efforts to elucidate risk for internalizing symptoms among adolescent girls.

title: Cyberostracism: effects of being ignored over the Internet.
abstract: Ostracism is such a widely used and powerful tactic that the authors tested whether people would be affected by it even under remote and artificial circumstances. In Study 1, 1,486 participants from 62 countries accessed the authors' on-line experiment on the Internet. They were asked to use mental visualization while playing a virtual tossing game with two others (who were actually computer generated and controlled). Despite the minimal nature of their experience, the more participants were ostracized, the more they reported feeling bad, having less control, and losing a sense of belonging. In Study 2, ostracized participants were more likely to conform on a subsequent task. The results are discussed in terms of supporting K. D. Williams's (1997) need threat theory of ostracism.

title: The Perceived Competence Scale for Children.
abstract: HARTER, SUSAN. The Perceived Competence Scale for Children. CmILD DEVELOPMENT, 1982, 53, 87-97. A new self-report instrument, the Perceived Competence Scale for Children, is described. Emphasis is placed on the assessment of a child's sense of competence across different domains, instead of viewing perceived competence as a unitary construct. 3 domains of competence, each constituting a separate subscale, were identified: (a) cognitive, (b) social, and (c) physical. A fourth subscale, general self-worth, independent of any particular skill domain, was included. A new question format was devised which provides a broader range of responses and reduces the tendency to give socially desirable responses. The psychometric properties of the scale are presented for third through ninth grades. Emphasis is placed on its factorial validity. Each subscale defines a separate factor, indicating that children make clear differentiations among these domains. The factor structure is extremely stable across this grade range. The scale is viewed as an alternative to those existing self-concept measures of questionable validity and reliability.

title: The Children's Attributional Style Interview: Developmental Tests of Cognitive Diathesis-Stress Theories of Depression
abstract: This paper presents an initial assessment of the Children's Attributional Style Interview (CASI), a newly designed measure for assessing attributional style in young children (age 5 and up). The CASI was used to conduct prospective tests of the reformulated helplessness (L. Y. Abramson, M. Seligman, & J. Teasdale, 1978) and the integrated hopelessness/self-esteem (G. I. Metalsky, T. E. Joiner, Jr., T. S. Hardin, & L. Y. Abramson, 1993) theories of depression in a sample of 147 5–10-year-old children. For comparison, the same tests were also conducted with the Children's Attributional Style Questionnaire-Revised (CASQ-R; N. J. Kaslow & S. Nolen-Hoeksema, 1991), a commonly used measure for assessing attributional style in older children (age 8 and up). The CASI evidenced support of the reformulated helplessness theory and partial support of the integrated hopelessness/self-esteem theory. The CASI also demonstrated good internal consistency. Thus, our findings provide initial support for the CASI as a methodologically sound measure of attributional style for children as young as 5 years old. Although preliminary, our findings also suggest possible developmental differences in how attributional style interacts with self-esteem and negative life stress. The CASI should prove to be a useful tool in furthering the understanding of the origins and development of attributional style in childhood, as well as its contribution to the understanding of the development and prevention of depressive symptomatology in children.

title: Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates
abstract: Functional MRI (fMRI) is 25 years old, yet surprisingly its most common statistical methods have not been validated using real data. Here, we used resting-state fMRI data from 499 healthy controls to conduct 3 million task group analyses. Using this null data with different experimental designs, we estimate the incidence of significant results. In theory, we should find 5% false positives (for a significance threshold of 5%), but instead we found that the most common software packages for fMRI analysis (SPM, FSL, AFNI) can result in false-positive rates of up to 70%. These results question the validity of a number of fMRI studies and may have a large impact on the interpretation of weakly significant neuroimaging results. The most widely used task functional magnetic resonance imaging (fMRI) analyses use parametric statistical methods that depend on a variety of assumptions. In this work, we use real resting-state data and a total of 3 million random task group analyses to compute empirical familywise error rates for the fMRI software packages SPM, FSL, and AFNI, as well as a nonparametric permutation method. For a nominal familywise error rate of 5%, the parametric statistical methods are shown to be conservative for voxelwise inference and invalid for clusterwise inference. Our results suggest that the principal cause of the invalid cluster inferences is spatial autocorrelation functions that do not follow the assumed Gaussian shape. By comparison, the nonparametric permutation test is found to produce nominal results for voxelwise as well as clusterwise inference. These findings speak to the need of validating the statistical methods being used in the field of neuroimaging.

title: An effect size primer: A guide for clinicians and researchers.
abstract: Increasing emphasis has been placed on the use of effect size reporting in the analysis of social science data. Nonetheless, the use of effect size reporting remains inconsistent, and interpretation of effect size estimates continues to be confused. Researchers are presented with numerous effect sizes estimate options, not all of which are appropriate for every research question. Clinicians also may have little guidance in the interpretation of effect sizes relevant for clinical practice. The current article provides a primer of effect size estimates for the social sciences. Common effect sizes estimates, their use, and interpretations are presented as a guide for researchers.

title: Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.
abstract: Depression is associated with interpersonal difficulties related to abnormalities in affective facial processing.



To map brain systems activated by sad facial affect processing in patients with depression and to identify brain functional correlates of antidepressant treatment and symptomatic response.



Two groups underwent scanning twice using functional magnetic resonance imaging (fMRI) during an 8-week period. The event-related fMRI paradigm entailed incidental affect recognition of facial stimuli morphed to express discriminable intensities of sadness.



Participants were recruited by advertisement from the local population; depressed subjects were treated as outpatients.



We matched 19 medication-free, acutely symptomatic patients satisfying DSM-IV criteria for unipolar major depressive disorder by age, sex, and IQ with 19 healthy volunteers.  After the baseline assessment, patients received fluoxetine hydrochloride, 20 mg/d, for 8 weeks.



Average activation (capacity) and differential response to variable affective intensity (dynamic range) were estimated in each fMRI time series. We used analysis of variance to identify brain regions that demonstrated a main effect of group (depressed vs healthy subjects) and a group x time interaction (attributable to antidepressant treatment). Change in brain activation associated with reduction of depressive symptoms in the patient group was identified by means of regression analysis. Permutation tests were used for inference.



Over time, depressed subjects showed reduced capacity for activation in the left amygdala, ventral striatum, and frontoparietal cortex and a negatively correlated increase of dynamic range in the prefrontal cortex. Symptomatic improvement was associated with reduction of dynamic range in the pregenual cingulate cortex, ventral striatum, and cerebellum.



Antidepressant treatment reduces left limbic, subcortical, and neocortical capacity for activation in depressed subjects and increases the dynamic range of the left prefrontal cortex. Changes in anterior cingulate function associated with symptomatic improvement indicate that fMRI may be a useful surrogate marker of antidepressant treatment response.

title: A Double Dissociation of Ventromedial Prefrontal Cortical Responses to Sad and Happy Stimuli in Depressed and Healthy Individuals
abstract: The ventromedial prefrontal cortex (VMPFC) is a region implicated in the assessment of the rewarding potential of stimuli and may be dysfunctional in major depressive disorder (MDD). The few studies examining prefrontal cortical responses to emotive stimuli in MDD have indicated increased VMPFC responses to pleasant images but decreased responses to sad mood provocation when compared with healthy individuals. We wished to corroborate these results by examining neural responses to personally relevant happy and sad stimuli in MDD and healthy individuals within the same paradigm.



Neural responses to happy and sad emotional stimuli (autobiographical memory prompts and congruent facial expressions) were measured using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) in MDD (n = 12) and healthy (n = 12) individuals.



Increased and decreased responses in VMPFC were observed in MDD and healthy individuals, respectively, to happy stimuli, whereas the pattern was reversed for MDD and healthy individual responses to sad stimuli. These findings were not explained by medication effects in depressed individuals.



These findings indicate a double dissociation of the pattern of VMPFC response to happy and sad stimuli in depressed and healthy individuals and suggest abnormal reward processing in MDD.

title: Amygdala hyperactivation and prefrontal hypoactivation in subjects with cognitive vulnerability to depression
abstract: The hopelessness theory (HT) of depression is a diathesis-stress theory which construes cognitive vulnerability (CV) to depression. Neuroimaging studies examining depression have implicated the amygdala as an important potential locus of dysfunction in the processing of salient threatening stimuli. However, little is known about neural activation in the brain of subjects with CV to depression. Medication-free major depressive disorder (MDD) subjects (N=29), never depressed subjects with CV (N=26), and demographically matched never depressed healthy control (HC) subjects (N=31) were scanned using functional magnetic resonance imaging (fMRI) while performing an emotional matching task. The MDD subjects showed elevated left amygdala responses and reduced left dorsolateral prefrontal cortex (dlPFC) activation levels relative to HC subjects. Similarly, CV subjects had greater activity in the amygdala bilaterally and lesser activation in the dlPFC bilaterally, relative to HC subjects. The present findings raise the possibility that cognitive vulnerability to depression might be characterized by hypoactivation of the prefrontal cortex and hyperactivation of the amygdala in response to emotional stimuli; our observations might provide a potential interpretation to explain the abnormalities in neural networks mediating cognitive modulation of emotions in individuals with cognitive vulnerability to depression.

title: Both of Us Disgusted in My Insula The Common Neural Basis of Seeing and Feeling Disgust
abstract: What neural mechanism underlies the capacity to understand the emotions of others? Does this mechanism involve brain areas normally involved in experiencing the same emotion? We performed an fMRI study in which participants inhaled odorants producing a strong feeling of disgust. The same participants observed video clips showing the emotional facial expression of disgust. Observing such faces and feeling disgust activated the same sites in the anterior insula and to a lesser extent in the anterior cingulate cortex. Thus, as observing hand actions activates the observer's motor representation of that action, observing an emotion activates the neural representation of that emotion. This finding provides a unifying mechanism for understanding the behaviors of others.

title: Depression is associated with increased sensitivity to signals of disgust: a functional magnetic resonance imaging study.
abstract: Emotions of fear and disgust are related to core symptoms of depression. The neurobiological mechanisms of these associations are poorly understood. This functional magnetic resonance imaging study aimed at examining the Blood oxygenation level dependent (BOLD) response to facial expressions of fear and disgust in patients with major depressive disorder. Nine patients in an episode of major depression and nine healthy controls underwent two functional magnetic resonance imaging experiments where they judged the gender of facial identities displaying different degrees (mild, strong) of fear or disgust, intermixed with non-emotional faces. Compared with healthy controls, patients with depression demonstrated greater activation in left insula, left orbito-frontal gyrus, left middle/inferior temporal gyrus, and right middle/inferior temporal gyrus to expressions of strong disgust. Depressed patients also demonstrated reduced activation in left inferior parietal lobe to mildly fearful faces. Enhanced activation to facial expressions of disgust may reflect an emotion processing bias that suggests high relevance of emotion of disgust to depression.

title: Executive Semantic Processing Is Underpinned by a Large-scale Neural Network: Revealing the Contribution of Left Prefrontal, Posterior Temporal, and Parietal Cortex to Controlled Retrieval and Selection Using TMS
abstract: To understand the meanings of words and objects, we need to have knowledge about these items themselves plus executive mechanisms that compute and manipulate semantic information in a task-appropriate way. The neural basis for semantic control remains controversial. Neuroimaging studies have focused on the role of the left inferior frontal gyrus (LIFG), whereas neuropsychological research suggests that damage to a widely distributed network elicits impairments of semantic control. There is also debate about the relationship between semantic and executive control more widely. We used TMS in healthy human volunteers to create “virtual lesions” in structures typically damaged in patients with semantic control deficits: LIFG, left posterior middle temporal gyrus (pMTG), and intraparietal sulcus (IPS). The influence of TMS on tasks varying in semantic and nonsemantic control demands was examined for each region within this hypothesized network to gain insights into (i) their functional specialization (i.e., involvement in semantic representation, controlled retrieval, or selection) and (ii) their domain dependence (i.e., semantic or cognitive control). The results revealed that LIFG and pMTG jointly support both the controlled retrieval and selection of semantic knowledge. IPS specifically participates in semantic selection and responds to manipulations of nonsemantic control demands. These observations are consistent with a large-scale semantic control network, as predicted by lesion data, that draws on semantic-specific (LIFG and pMTG) and domain-independent executive components (IPS).

title: Functional imaging studies of emotion regulation: a synthetic review and evolving model of the cognitive control of emotion
abstract: This paper reviews and synthesizes functional imaging research that over the past decade has begun to offer new insights into the brain mechanisms underlying emotion regulation. Toward that end, the first section of the paper outlines a model of the processes and neural systems involved in emotion generation and regulation. The second section surveys recent research supporting and elaborating the model, focusing primarily on studies of the most commonly investigated strategy, which is known as reappraisal. At its core, the model specifies how prefrontal and cingulate control systems modulate activity in perceptual, semantic, and affect systems as a function of one's regulatory goals, tactics, and the nature of the stimuli and emotions being regulated. This section also shows how the model can be generalized to understand the brain mechanisms underlying other emotion regulation strategies as well as a range of other allied phenomena. The third and last section considers directions for future research, including how basic models of emotion regulation can be translated to understand changes in emotion across the life span and in clinical disorders.

title: Adolescents' emotion regulation in daily life: links to depressive symptoms and problem behavior.
abstract: This study examined links between emotion regulation and adjustment in a sample of 152 adolescents in Grades 7 (M age = 12) and 10 (M age = 15). Emotion regulation was assessed using the experience sampling method, in which adolescents provided multiple reports about the intensity, lability, and strategies used to regulate negative emotions across 1 week. Adolescents also completed self-report measures of adjustment. Adolescents who reported more intense and labile emotions and less effective regulation of these emotions also reported more depressive symptoms and problem behavior. Responding to negative emotions with disengagement (e.g., denial) or involuntary engagement (e.g., rumination) was less effective in regulating negative affect, and greater use of these strategies was related to higher levels of depressive symptoms and problem behavior.

title: Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies.
abstract: In recent years, an explosion of neuroimaging studies has examined cognitive reappraisal, an emotion regulation strategy that involves changing the way one thinks about a stimulus in order to change its affective impact. Existing models broadly agree that reappraisal recruits frontal and parietal control regions to modulate emotional responding in the amygdala, but they offer competing visions of how this is accomplished. One view holds that control regions engage ventromedial prefrontal cortex (vmPFC), an area associated with fear extinction, that in turn modulates amygdala responses. An alternative view is that control regions modulate semantic representations in lateral temporal cortex that indirectly influence emotion-related responses in the amygdala. Furthermore, while previous work has emphasized the amygdala, whether reappraisal influences other regions implicated in emotional responding remains unknown. To resolve these questions, we performed a meta-analysis of 48 neuroimaging studies of reappraisal, most involving downregulation of negative affect. Reappraisal consistently 1) activated cognitive control regions and lateral temporal cortex, but not vmPFC, and 2) modulated the bilateral amygdala, but no other brain regions. This suggests that reappraisal involves the use of cognitive control to modulate semantic representations of an emotional stimulus, and these altered representations in turn attenuate activity in the amygdala.

title: Default-Mode and Task-Positive Network Activity in Major Depressive Disorder: Implications for Adaptive and Maladaptive Rumination
abstract: Major depressive disorder (MDD) has been associated reliably with ruminative responding; this kind of responding is composed of both maladaptive and adaptive components. Levels of activity in the default-mode network (DMN) relative to the task-positive network (TPN), as well as activity in structures that influence DMN and TPN functioning, may represent important neural substrates of maladaptive and adaptive rumination in MDD.



We used a unique metric to estimate DMN dominance over TPN from blood oxygenation level-dependent data collected during eyes-closed rest in 17 currently depressed and 17 never-disordered adults. We calculated correlations between this metric of DMN dominance over TPN and the depressive, brooding, and reflective subscales of the Ruminative Responses Scale, correcting for associations between these measures both with one another and with severity of depression. Finally, we estimated and compared across groups right fronto-insular cortex (RFIC) response during initiations of ascent in DMN and in TPN activity.



In the MDD participants, increasing levels of DMN dominance were associated with higher levels of maladaptive, depressive rumination and lower levels of adaptive, reflective rumination. Moreover, our RFIC state-change analysis showed increased RFIC activation in the MDD participants at the onset of increases in TPN activity; conversely, healthy control participants exhibited increased RFIC response at the onset of increases in DMN activity.



These findings support a formulation in which the DMN undergirds representation of negative, self-referential information in depression, and the RFIC, when prompted by increased levels of DMN activity, initiates an adaptive engagement of the TPN.

title: Imbalance of default mode and regulatory networks during externally focused processing in depression.
abstract: Attentional control difficulties likely underlie rumination, a core cognitive vulnerability in major depressive disorder (MDD). Abnormalities in the default mode, executive and salience networks are implicated in both rumination and attentional control difficulties in MDD. In the current study, individuals with MDD (n = 16) and healthy controls (n = 16) completed tasks designed to elicit self-focused (ruminative) and externally-focused thinking during fMRI scanning. The MDD group showed greater default mode network connectivity and less executive and salience network connectivity during the external-focus condition. Contrary to our predictions, there were no differences in connectivity between the groups during the self-focus condition. Thus, it appears that when directed to engage in self-referential thinking, both depressed and non-depressed individuals similarly recruit networks supporting this process. In contrast, when instructed to engage in non-self-focused thought, non-depressed individuals show a pattern of network connectivity indicative of minimized self-referential processing, whereas depressed individuals fail to reallocate neural resources in a manner consistent with effective down regulation of self-focused thought. This is consistent with difficulties in regulating self-focused thinking in order to engage in more goal-directed behavior that is seen in individuals with MDD.

title: Development of neural systems for processing social exclusion from childhood to adolescence.
abstract: Adolescence is a period of development in which peer relationships become especially important. A computer-based game (Cyberball) has been used to explore the effects of social exclusion in adolescents and adults. The current functional magnetic resonance imaging (fMRI) study used Cyberball to extend prior work to the cross-sectional study of younger children and adolescents (7 to 17 years), identifying age-related changes in the neural correlates of social exclusion across the important transition from middle childhood into adolescence. Additionally, a control task illustrated the specificity of these age-related changes for social exclusion as distinct from expectancy violation more generally. During exclusion, activation in and functional connectivity between ventrolateral prefrontal cortex and ventral anterior cingulate cortex increased with age. These effects were specific to social exclusion and did not exist for expectancy violation. Our results illustrate developmental changes from middle childhood through adolescence in both affective and regulatory brain regions during social exclusion.

title: Neural correlates of social exclusion across ages: A coordinate-based meta-analysis of functional MRI studies
abstract: Given the recent surge in functional neuroimaging studies on social exclusion, the current study employed activation likelihood estimation (ALE) based meta‐analyses to identify brain regions that have consistently been implicated across different experimental paradigms used to investigate exclusion. We also examined the neural correlates underlying Cyberball, the most commonly used paradigm to study exclusion, as well as differences in exclusion‐related activation between developing (7–18 years of age, from pre‐adolescence up to late adolescence) and emerging adult (broadly defined as undergraduates, including late adolescence and young adulthood) samples. Results revealed involvement of the bilateral medial prefrontal and posterior cingulate cortices, right precuneus and left ventrolateral prefrontal cortex across the different paradigms used to examine social exclusion; similar activation patterns were identified when restricting the analysis to Cyberball studies. Investigations into age‐related effects revealed that ventrolateral prefrontal activations identified in the full sample were driven by (i.e. present in) developmental samples, while medial prefrontal activations were driven by emerging adult samples. In addition, the right ventral striatum was implicated in exclusion, but only in developmental samples. Subtraction analysis revealed significantly greater activation likelihood in striatal and ventrolateral prefrontal clusters in the developmental samples as compared to emerging adults, though the opposite contrast failed to identify any significant regions. Findings integrate the knowledge accrued from functional neuroimaging studies on social exclusion to date, highlighting involvement of lateral prefrontal regions implicated in regulation and midline structures involved in social cognitive and self‐evaluative processes across experimental paradigms and ages, as well as limbic structures in developing samples specifically. HighlightsMeta‐analysis of studies examining the neural correlates of social exclusion.Recruits medial and lateral prefrontal, and midline posterior parietal cortices.Neural differences identified between developmental and emerging‐adult samples.Unique role of ventral striatum in developmental samples.

title: Neural correlates of social exclusion during adolescence: understanding the distress of peer rejection.
abstract: Developmental research has demonstrated the harmful effects of peer rejection during adolescence; however, the neural mechanisms responsible for this salience remain unexplored. In this study, 23 adolescents were excluded during a ball-tossing game in which they believed they were playing with two other adolescents during an fMRI scan; in reality, participants played with a preset computer program. Afterwards, participants reported their exclusion-related distress and rejection sensitivity, and parents reported participants' interpersonal competence. Similar to findings in adults, during social exclusion adolescents displayed insular activity that was positively related to self-reported distress, and right ventrolateral prefrontal activity that was negatively related to self-reported distress. Findings unique to adolescents indicated that activity in the subgenual anterior cingulate cortex (subACC) related to greater distress, and that activity in the ventral striatum related to less distress and appeared to play a role in regulating activity in the subACC and other regions involved in emotional distress. Finally, adolescents with higher rejection sensitivity and interpersonal competence scores displayed greater neural evidence of emotional distress, and adolescents with higher interpersonal competence scores also displayed greater neural evidence of regulation, perhaps suggesting that adolescents who are vigilant regarding peer acceptance may be most sensitive to rejection experiences.

title: Does low self-esteem enhance social pain? The relationship between trait self-esteem and anterior cingulate cortex activation induced by ostracism.
abstract: According to sociometer theory, self-esteem serves as a barometer of the extent to which individuals are socially included or excluded by others. We hypothesized that trait self-esteem would be related to social pain responsiveness, and we used functional magnetic resonance imaging to experimentally investigate this potential relationship. Participants (n = 26) performed a cyberball task, a computerized game of catch during which the participants were excluded from the game. Participants then rated the degree of social pain experienced during both inclusion in and exclusion from the game. Individuals with lower trait self-esteem reported increased social pain relative to individuals with higher trait self-esteem, and such individuals also demonstrated a greater degree of dorsal anterior cingulate cortex activation. A psychophysiological interaction analysis revealed a positive connectivity between the dorsal anterior cingulate and prefrontal cortices for the lower trait self-esteem group, and a corresponding negative connectivity for the higher trait self-esteem group. Heightened dorsal anterior cortex activity and a corresponding connection with the prefrontal cortex might be one possible explanation for the greater levels of social pain observed experienced by individuals with low trait self-esteem.

title: The face of rejection: Rejection sensitivity moderates dorsal anterior cingulate activity to disapproving facial expressions
abstract: Previous research has examined neural responses to threatening facial expressions such as those displaying anger, fear, and disgust. Here, we examined neural responses to a different type of threatening facial expression that primarily signifies a threat to social connection, namely a “disapproving” facial expression. We hypothesized that neural responses to disapproving facial expressions would be moderated by individual differences in rejection sensitivity. Using functional magnetic resonance imaging (fMRI), we scanned participants while they viewed brief video clips of facial expressions depicting disapproval, anger, and disgust. As expected, all three expressions yielded bilateral amygdala activation relative to a resting baseline. Additionally, individuals who scored higher on a measure of rejection sensitivity exhibited greater dorsal anterior cingulate cortex activity in response to disapproving facial expressions, but not in response to anger or disgust facial expressions. Results suggest that, at the neural level, individuals high in rejection sensitivity may be more sensitive to facial expressions signaling potential rejection, but not to threatening facial expressions in general. Results also suggest that disapproving facial expressions convey a distinct type of threat and should be considered in future studies of socially threatening facial expressions.

title: Deep Brain Stimulation for Treatment-Resistant Depression
abstract: Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical s...

title: Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression.
abstract: Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-μs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.

title: A Quantitative Meta-Analysis of Functional Imaging Studies of Social Rejection
abstract: Early neuroimaging studies using Cyberball suggested that social rejection activated the pain matrix, as identified in studies of physical pain. However, these early studies were characterized by small sample sizes. Our statistical multi-level kernel density analysis (MKDA) of Cyberball neuroimaging studies with 244 participants fails to support the claim that social rejection operates on the same pain matrix as nociceptive stimuli, questioning whether social pain is more figurative or literal. We also performed an MKDA of the neuroimaging studies of reliving a romantic rejection to test whether the pain matrix was activated if the rejection were more meaningful. Results again failed to support the notion that rejection activates the neural matrix identified in studies of physical pain. Reliving an unwanted rejection by a romantic partner was significantly characterized by activation within and beyond the “Cyberball” brain network, suggesting that the neural correlates of social pain are more complex than previously thought.