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Apophenia is the tendency to falsely detect meaningful relationships and may indicate susceptibility to more extreme expressions on the psychotic spectrum. This pilot investigated the fragmented ambiguous object task (FAOT), a new measure designed to assess apophenia behaviorally in a sample of adolescents with and without mood disorders using an image recognition task. Our primary hypothesis was that increased image recognition would be associated with PID-5 psychoticism. Participants were 33 (79% female) adolescents with (n = 18) and without (n = 15) mood disorders. Consistent with predictions, increased recognition of ambiguous images correlated positively with psychoticism. There was also moderate evidence for long-term stability of FAOT apophenia scores over time (mean interval of approximately 10 months). These findings offer preliminary evidence that the FAOT may be reflective of underlying psychoticism in our target population.

BACKGROUND. Dysregulated stress responsivity is implicated in adolescent risk for depression and self-injurious thoughts and behaviors (STBs). However, studies often examine levels of the stress response in isolation, precluding understanding of how coordinated disturbance across systems confers risk. The current study utilized a novel person-centered approach to identify stress correspondence profiles and linked them to depressive symptoms, STBs, and neural indices of self-regulatory capacity. METHOD. Adolescents with and without a major depressive disorder diagnosis (N=162, M(age)=16.54, SD=1.96, 72.8% White, 66.5% female) completed the Trier Social Stress Test (TSST), questionnaires, and clinical interviews. Stress experience (self-report), expression (observed), and physiology (salivary cortisol) were assessed during the experimental protocol. Adolescents also underwent a magnetic resonance imaging scan. RESULTS. Multitrajectory modeling revealed four profiles. High Experience–High Expression–Low Physiology (i.e., lower stress correspondence) adolescents were more likely to report depressive symptoms, lifetime nonsuicidal self-injury, and suicidal ideation relative to all other subgroups reflecting higher stress correspondence: Low Experience–Low Expression–Low Physiology, Moderate Experience–Moderate Expression–Moderate Physiology, High Experience–High Expression–High Physiology. High Experience–High Expression–Low Physiology adolescents also exhibited less positive amygdala–ventromedial prefrontal cortex resting state functional connectivity relative to Moderate Experience–Moderate Expression–Moderate Physiology. LIMITATIONS. Data were cross-sectional, precluding inference about our profiles as etiological risk factors or mechanisms of risk. CONCLUSIONS. Findings illustrate meaningful heterogeneity in adolescent stress correspondence with implications for multimodal, multilevel assessment and outcome monitoring in depression prevention and intervention efforts.

Non-suicidal self-injury (NSSI) defies the core purpose of the brain and body’s threat processing and response system: self-preservation and protection from harm. The hypothalamic-pituitary-adrenal (HPA) axis coordinates the endocrine response to threats. Preliminary evidence suggests that individuals who engage in NSSI demonstrate blunted cortisol responses to stressors and possibly elevations in basal cortisol. The neural threat system involves the amygdala, anterior cingulate cortex (ACC), prefrontal cortex (PFC), and insula. Individuals with a history of NSSI have been shown to have structural alterations in and between the ACC, insula, and amygdala. Functional connectivity between the amygdala and PFC has been shown to be altered in adolescents with a history of NSSI as well. Further, individuals with a history of NSSI have been shown to have increased amygdala activation in response to emotional stimuli. Work that integrates multiple modes of measuring stress response has shown discordance between the HPA axis response, experience of stress, and expression of stress among those with more severe NSSI. More work is needed to disentangle discordance within the threat processing system. Additionally, there is a need for more nuanced understanding of (a) environmental mechanisms of risk and protection, (b) implications of sustained engagement in NSSI, and (c) a broader array of pathology as it relates to biological threat-system disturbances for those who engage in NSSI. Future work on NSSI should explore ways to mitigate the impact of risk factors and leverage the protective factors and neurobiological and psychological underpinnings of NSSI to identify novel treatment modalities.

Objective: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behavior. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. Method: Here, we examine this issue through two approaches: (a) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (b) by pooling data (N ∼ 6,000 participants) from cohorts from the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Major Depressive Disorder and ENIGMA–Suicidal Thoughts and Behaviour working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behavior. Results: We observed moderate-to-high correlations between measures, consistent with the wide range (κ range: 0.15–0.97; r range: 0.21–0.94) reported in the literature. Two common multi-item instruments, the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicidal Ideation were highly correlated with each other (r = 0.83). Sensitivity analyses identified sources of heterogeneity such as the time frame of the instrument and whether it relies on self-report or a clinical interview. Finally, construct-specific analyses suggest that suicide ideation items from common psychiatric questionnaires are most concordant with the suicide ideation construct of multi-item instruments. Conclusions: Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behavior but share a modest core factor with single suicidal ideation items. Retrospective, multisite collaborations including distinct instruments should be feasible provided they harmonize across instruments or focus on specific constructs of suicidality.

BackgroundSuicide is the second-leading cause of death in youth. Understanding the neural correlates of suicide ideation (SI) in children is crucial to ongoing efforts to understand and prevent youth suicide. This study characterized key neural networks during rest and emotion task conditions in an epidemiologically informed sample of children who report current, past, or no SI.MethodsData are from the adolescent brain cognitive development study, including 8248 children (ages 9–10; mean age = 119.2 months; 49.2% female) recruited from the community. Resting-state functional connectivity (RSFC) and activation to emotional stimuli in the salience (SN) and default mode (DMN) networks were measured through fMRI. Self-reported SI and clinical profiles were gathered. We examined the replicability of our model results through repeated sub-sample reliability analyses.ResultsChildren with current SI (2.0%), compared to those without any past SI, showed lower DMN RSFC (B = −0.267, p < 0.001) and lower DMN activation in response to negative as compared to neutral faces (B = −0.204, p = 0.010). These results were robust to the effects of MDD, ADHD, and medication use. Sub-sample analysis further supported the robustness of these results. We did not find support for differences in SN RSFC or in SN activation to positive or negative stimuli for children with or without SI.ConclusionsResults from a large brain imaging study using robust statistical approaches suggest aberrant DMN functioning in children with current suicide ideation. Findings suggest potential mechanisms that may be targeted in suicide prevention efforts.

Abstract. Background: Suicide prevention public service announcements (PSAs) help to disseminate information about suicide and help-seeking options. However, little is known about how individuals at risk for suicide recall PSAs. Aims: The current project assessed which features of suicide prevention PSAs are recalled by young adult participants and whether there are differences between those who are at low or high risk for suicide. Method: Participants ( N = 140) viewed a simulated suicide prevention billboard that consisted of a main message, help-seeking message, and graphical features. Participants provided written recollections of the billboard features approximately 15 min post-viewing, which were coded and analyzed. Results: High-risk participants were significantly less likely than low-risk participants to include a description of the help-seeking message in their written recall. Few group differences were noted in the recall of the main message or graphical features. Limitations: Recall was limited to short-term recall based on a single exposure. Efforts to enhance internal validity (e.g., measurement of suicide risk) and external validity (e.g., a balanced sample regarding sex and race) are recommended. Conclusions: Results suggest that new tactics may need to be considered when developing suicide prevention messages, including crafting help-seeking messages that are more easily committed to memory for target audiences.

Clinical psychology is a young science. Despite immense growth over 100+ years, human suffering from mental health conditions remains extensive, and core scientific issues in our field continue to be the subject of ongoing debate. Clinical practice depends on the growth of our research base for elucidating etiology, systematic improvements in provision of mental health care, improvements in public health, and credibility with clients and the larger public. Clinical psychology training programs must afford students opportunities to specialize and develop expertise in their chosen research domain. Such opportunities will help students develop into independent scientists, clinicians, and/or administrators who produce knowledge and may translate it to improve clinical care. To meet this aim, we propose that clinical psychology training standards accommodate increased scientific and research training by reducing generalist requirements and increasing curricular flexibility for students. These changes are not necessarily proposed for all clinical psychology training programs, but for those that are keen to train students to develop and apply scientific knowledge to understand, assess, and ameliorate mental illness. Our proposed changes would allow accredited clinical psychology programs additional latitude to train their students in clinical research; make high-quality mental health care available to more people at lower cost; allow clinical psychologists more opportunities to work at the level of the clinic, system, policy, or laboratory; and thereby accelerate scientific discovery and translation to understand and reduce mental health burdens in our society.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

The childhood-to-adolescence transition is a notable period of change including pubertal development, neurodevelopment, and psychopathology onset, that occurs in divergent patterns between sexes. This study examined the effects of sex and puberty on cortical thickness (CT) in children and explored whether CT changes over time related to emergence of psychopathology in early adolescence.We used longitudinal data (baseline ages 9-10 and Year 2 [Y2] ages 11-12) from the ABCD Study (n = 9985). Linear and penalized function-on-function regressions modeled the impact of puberty, as it interacts with sex, on CT. Focusing on regions that showed sex differences, linear and logistic regressions modeled associations between change in CT and internalizing problems and suicide ideation.We identified significant sex differences in the inverse relation between puberty and CT in fifteen primarily posterior brain regions. Nonlinear pubertal effects across age were identified in the fusiform, isthmus cingulate, paracentral, and precuneus. All effects were stronger for females relative to males during this developmental window. We did not identify associations between CT change and early adolescent clinical outcomes.During this age range, puberty is most strongly associated with regional changes in CT in females, which may have implications for the later emergence of psychopathology.

Growing evidence suggests that emotion socialization may be disrupted by maternal depression. However, little is known about emotion-related parenting by mothers with bipolar disorder or whether affective modeling in early childhood is linked to young adults’ recollections of emotion socialization practices. The current study investigates emotion socialization by mothers with histories of major depression, bipolar disorder, or no mood disorder. Affective modeling was coded from parent–child interactions in early childhood and maternal responses to negative emotions were recollected by young adult offspring (n = 131, 59.5% female, M age = 22.16, SD = 2.58). Multilevel models revealed that maternal bipolar disorder was associated with more neglecting, punishing, and magnifying responses to children's emotions, whereas maternal major depression was associated with more magnifying responses; links between maternal diagnosis and magnifying responses were robust to covariates. Young adult recollections of maternal responses to emotion were predicted by affective modeling in early childhood, providing preliminary validity evidence for the Emotions as a Child Scale. Findings provide novel evidence that major depression and bipolar disorder are associated with altered emotion socialization and that maternal affective modeling in early childhood prospectively predicts young adults’ recollections of emotion socialization in families with and without mood disorder.

Background: Current theory suggests that treatment-resistant depression (TRD) involves impaired neuroplasticity resulting in cognitive and neural rigidity, and that clinical improvement may require increasing brain flexibility and adaptability. Aims: In this hypothesis-generating study, we sought to identify preliminary evidence of brain flexibility correlates of clinical change within the context of an open-label ketamine trial in adolescents with TRD, focusing on two promising candidate markers of neural flexibility: (a) entropy of resting-state functional magnetic resonance imaging (fMRI) signals; and (b) insulin-stimulated phosphorylation of mammalian target of rapamycin (mTOR) and glycogen synthase-3-beta (GSK3β) in peripheral blood mononuclear cells. Methods: We collected resting-state functional magnetic resonance imaging data and blood samples from 13 adolescents with TRD before and after a series of six ketamine infusions over 2 weeks. Usable pre/post ketamine data were available from 11 adolescents for imaging and from 10 adolescents for molecular signaling. We examined correlations between treatment response and changes in the central and peripheral flexibility markers. Results: Depression reduction correlated with increased nucleus accumbens entropy. Follow-up analyses suggested that physiological changes were associated with treatment response. In contrast to treatment non-responders ( n=6), responders ( n=5) showed greater increase in nucleus accumbens entropy after ketamine, together with greater post-treatment insulin/mTOR/GSK3β signaling. Conclusions: These data provide preliminary evidence that changes in neural flexibility may underlie symptom relief in adolescents with TRD following ketamine. Future research with adequately powered samples is needed to confirm resting-state entropy and insulin-stimulated mTOR and GSK3β as brain flexibility markers and candidate targets for future clinical trials. Clinical trial name: Ketamine in adolescents with treatment-resistant depression URL: https://clinicaltrials.gov/ct2/show/NCT02078817 Registration number: NCT02078817

Precision medicine approaches hold tremendous promise to advance current clinical practice by providing information about which individuals will benefit from which treatments. This pilot study evaluated if baseline structure and function of the salience and emotion brain regions implicated in adolescent depression, specifically the amygdala and anterior cingulate cortex (ACC), predict response to Interpersonal Psychotherapy for Depressed Adolescents (IPT-A). Adolescents (n = 15; mean age = 14.5 (1.6); 80.0% female) diagnosed with a depressive disorder completed brain scans before the start of a 16 week trial of IPT-A. Clinical measures assessing depressive symptoms were completed before, during, and after a trial of therapy. Results show that at baseline, greater ACC activation in the context of an emotion-matching task and greater amygdala-ACC resting-state functional connectivity was related to greater improvement in depression symptoms. There was minimal evidence that brain structure predicted changes in depressive symptoms. The present study is the first to evaluate neural predictors of IPT-A response. While the results are preliminary, these findings suggest some avenues for future research to pursue in the hopes that more will benefit from treatment.

Native American and multiracial youth experience elevated risk for suicide ideation (SI) and suicide attempts (SA); however, intersectional identities are often unexamined in suicide research.We examined the prevalence of SI and SA, and the impact of intersectional identities (sex, sexual minority identity, and economic insecurity) on these rates, in 496 biracial Black-Native American, 2,804 Native American, 14,220 Black, 5,569 biracial Native American-White, 4,076 biracial Black-White, and 118,816 White youth who participated in the Minnesota Student Survey.Black-Native American youth reports of SI and SA resembled other Native American youth and were significantly higher than those reported by Black, White, and Black-White (SA only) youth. While sexual minority youth reported higher rates of SI and SA than heterosexual youth, this difference between sexual minority and heterosexual Black-Native American youth was smaller as compared to their peers.Though they largely resemble their mono/biracial Native American peers, Black-Native American youth show some distinct patterns of SA when accounting for their intersectional identities. Despite presumed similarities in systemic risk factors, Black and Black-Native American youth differ considerably in reported suicidality. The experiences of Black-Native American teens warrant further examination.

The NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome is a node of intracellular stress pathways and a druggable target which integrates mitochondrial stress and inflammatory cascades. While a body of evidence suggests the involvement of the NLRP3 inflammasome in numerous diseases, a lack of reliable measurement techniques highlights the need for a robust assay using small quantities of biological samples. We present a literature overview on peripheral activation of the NLRP3 inflammasome in mood disorders, then outline a process to develop and validate a robust assay to measure baseline and activated intracellular levels of “apoptosis-associated speck-like protein containing a CARD” (ASC) as a key component of an inflammatory profile in peripheral blood mononuclear cells (PBMC). A consistent association between high NLRP3 mRNA levels and relevant cytokines was seen in the literature. Using our method to measure ASC, stimulation of PBMC with lipopolysaccharide and nigericin or adenosine triphosphate resulted in microscopic identification of intracellular ASC specks, as well as interleukin 1 (IL-1) beta and caspase-1 p10 in the periphery. This was abolished by dose-dependent pre-treatment with 100 nM MCC950. We also report the use of this technique in a small pilot sample from patients with bipolar disorder and depressive disorders. The results show that levels of intracellular ASC and IL-1 beta are sensitive to change upon activation and maintained over time, which may be used to improve the detection of NLRP3 activation and guide personalized therapeutic strategy in the treatment of patients.

The human brain is always active; it wanders freely during rest as well as when we lose focus during tasks. Mind-wandering encompasses spontaneous thinking, such as processing recent experiences, problem solving, and achieving insights. Understanding this unconstrained brain activity may lead to clues about the neural mechanisms of mental health problems. Brain networks implicated in mind-wandering include the default mode network (DMN), the salience network, and task-positive networks including the frontoparietal control network and dorsal attention network.1 Given that these networks mature during adolescence, coinciding with a time notable for the emergence of mental health problems, quantifying and examining the neural correlates of mind-wandering in adolescents with psychopathology may shed light on how the healthy and pathological brain functions and point to possible methods of intervening.

ObjectiveIdentifying brain differences associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and generating effective approaches to early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth.MethodsFirst, we examined associations among regional brain structure and STBs, which were assessed in six samples of youth with mood disorders, using the Columbia Suicide Severity Rating Scale (C-SSRS;N=577). Second, we combined this sample with a larger sample (total 21 sites) in which STBs were assessed using various instruments. MRI metrics were compared among healthy controls without STBs (HC;N=688), clinical controls without STBs (CC;N=648), and young people with psychiatric diagnoses and current suicidal ideation (N=406). In separate analyses, MRI metrics were compared among HCs (N=335), CCs (N=768), and suicide attempters (N=254).ResultsIn the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and history of actual suicide attempts (N=163) than those without (N=394; FDR-pd=.334). When expanding to more clinically heterogeneous samples, we also found lower surface area of the frontal pole in those with a history of suicide attempts (Cohen’sd=.22).ConclusionsLower frontal pole surface area may represent a vulnerability for a suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.

ObjectiveA major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behaviour. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia.MethodHere, we examine this issue through two approaches: (i) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments; and (ii) by pooling data (N∼6,000 participants) from cohorts from the ENIGMA-Major Depressive Disorder (ENIGMA-MDD) and ENIGMA-Suicidal Thoughts and Behaviour (ENIGMA-STB) working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behaviour.ResultsOur results suggested a pattern of moderate-to-high correlations between instruments, consistent with the wide range of correlations, r=0.22-0.97, reported in the literature. Two common complex instruments, the Columbia Suicide Severity Rating Scale (C-SSRS) and the Beck Scale for Suicidal Ideation (SSI), were highly correlated with each other (r=0.83), as were suicidal ideation items from common depression severity questionnaires.ConclusionsOur findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behaviour, but share a core factor with single suicidal ideation items found in depression severity questionnaires. Multi-site collaborations including cohorts that used distinct instruments for suicide risk assessment should be feasible provided that they harmonise across instruments or focus on specific constructs of suicidal thoughts or behaviours.Key pointsQuestion: To inform future suicide research in multi-site international consortia, it is important to examine how different suicide measures relate to each other and whether they can be used interchangeably.Findings: Findings suggest detailed instruments (such as the Columbia Suicide Severity Rating Scale and Beck Scale for Suicidal Ideation) provide valuable information on suicidal thoughts and behaviour, and share a core factor with items on suicidal ideation from depression severity rating scale (such as the Hamilton Depression Rating Scale or the Beck Depression Inventory).Importance: Results from international collaborations can mitigate biases by harmonising distinct suicide risk assessment instruments.Next steps: Pooling data within international suicide research consortia may reveal novel clinical, biological and cognitive correlates of suicidal thoughts and/or behaviour.

Nonsuicidal self-injury (NSSI) is a common but poorly understood phenomenon in adolescents. This study examined the Sustained Threat domain in female adolescents with a continuum of NSSI severity (N = 142). Across NSSI lifetime frequency and NSSI severity groups (No + Mild NSSI, Moderate NSSI, Severe NSSI), we examined physiological, self-reported and observed stress during the Trier Social Stress Test; amygdala volume; amygdala responses to threat stimuli; and resting-state functional connectivity (RSFC) between amygdala and medial prefrontal cortex (mPFC). Severe NSSI showed a blunted pattern of cortisol response, despite elevated reported and observed stress during TSST. Severe NSSI showed lower amygdala–mPFC RSFC; follow-up analyses suggested that this was more pronounced in those with a history of suicide attempt for both moderate and severe NSSI. Moderate NSSI showed elevated right amygdala activation to threat; multiple regressions showed that, when considered together with low amygdala–mPFC RSFC, higher right but lower left amygdala activation predicted NSSI severity. Patterns of interrelationships among Sustained Threat measures varied substantially across NSSI severity groups, and further by suicide attempt history. Study limitations include the cross-sectional design, missing data, and sampling biases. Our findings highlight the value of multilevel approaches in understanding the complexity of neurobiological mechanisms in adolescent NSSI.

One of the most consistent biological findings in the study of affective disorders is that those with depression commonly show abnormal cortisol response, which suggests dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Children of parents with mood disorders offer the opportunity to explore the biological pathways that may confer risk for psychopathology. This review explores basal and reactive cortisol in the offspring of parents who are currently depressed or have had a history of a depressive or bipolar disorder. Using PRISMA guidelines, search terms yielded 2002 manuscripts. After screening, 87 of these manuscripts were included. Results from the literature suggest that while the degree and direction of dysregulation varies, offspring of a parent with depression tend to show elevations in both basal (particularly morning and evening) and reactive (tentatively for social stressors) cortisol levels. There were few studies focused on offspring of parents with bipolar disorder. This review also discusses implications and recommendations for future research regarding the HPA axis in the intergenerational transmission of depressive disorders.