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Objective: Major depressive disorder (MDD) occurs frequently in adolescents, but the neurobiology of depression in youth is poorly understood. Structural neuroimaging studies in both adult and pediatric populations have implicated frontolimbic neural networks in the pathophysiology of MDD. Diffusion tensor imaging (DTI), which measures white matter (WM) microstructure, is a promising tool for examining neural connections and how they may be abnormal in MDD.Method: We used two separate approaches to analyze DTI data in adolescents with MDD (n = 14) compared with healthy volunteers (n = 14).Results: The first, hypothesis-driven approach was to use probabilistic tractography to delineate tracts arising from the subgenual anterior cingulate cortex (ACC). Adolescents with MDD demonstrated lower fractional anisotropy (FA) in the WM tract connecting subgenual ACC to amygdala in the right hemisphere. The second, exploratory approach was to conduct a voxelwise comparison of FA. This analysis revealed 10 clusters where adolescents with MDD had significantly lower (uncorrected) FA than the healthy group within WM tracts including right and left uncinate and supragenual cingulum.Conclusions: These preliminary data support the hypothesis that altered WM microstructure in frontolimbic neural pathways may contribute to the pathophysiology of MDD in adolescents. [ABSTRACT FROM AUTHOR]

In visual perception, an effect known as surround suppression occurs wherein the apparent contrast of a center stimulus is reduced when it is presented within a higher-contrast surrounding stimulus. Many key aspects of visual perception involve surround suppression, yet the neuromodulatory processes involved remain unclear. Psilocybin is a serotonergic psychedelic compound known for its robust effects on visual perception, particularly texture, color, object, and motion perception. We asked whether surround suppression is altered under peak effects of psilocybin. Using a contrast-matching task with different center-surround stimulus configurations, we measured surround suppression after 25 mg of psilocybin compared with placebo (100 mg niacin). Data on harms were collected, and no serious adverse events were reported. After taking psilocybin, participants (n = 6) reported stronger surround suppression of perceived contrast compared to placebo. Furthermore, we found that the intensity of subjective psychedelic visuals induced by psilocybin correlated positively with the magnitude of surround suppression. We note the potential relevance of our findings for the field of psychiatry, given that studies have demonstrated weakened visual surround suppression in both major depressive disorder and schizophrenia. Our findings are thus relevant to understanding the visual effects of psilocybin, and the potential mechanisms of visual disruption in mental health disorders.

Depression is a serious public health problem that often emerges during adolescence. Many adolescents do not respond to standard treatments, necessitating the development of novel interventions. We conducted a preliminary study to assess the impact of a novel creative arts intervention on depression and well-being in adolescents. In this quasi-experimental study, 69 adolescents 12-17 years completed an 8-day "Creativity Camp" intervention encompassing multiple creative activities. Self-report questionnaires to measure depression, anxiety, and well-being were administered at five time points to allow examination of change across multiple temporal segments: the 2 weeks before the intervention, the 2 weeks during the intervention, the 2 weeks after the intervention, and the 6 months after the intervention. Adolescents were assigned to one of two groups to compare changes observed during the 2 week before-intervention period (Group A) to the changes observed during the intervention period (pre-post intervention) (Group B). According to both parent and child reports, pre-to-post-intervention, mean adolescent depressive symptoms significantly decreased, and these changes were sustained 2 weeks after the intervention and (according to parents) at the 6-month follow-up. There was preliminary evidence for improved well-being at post-intervention. Comparison of Group A's changes during the before-intervention period to Group B's changes pre-post intervention was significant for parent-reported depression. Preliminary evidence suggests that the Creativity Camp intervention may positively impact adolescent depression and well-being. This evidence highlights the importance of investigating and implementing treatment approaches focusing on creative arts for adolescents with depression., (© 2024. The Author(s).)

Dante Cicchetti propelled forward the field of developmental psychopathology by advancing this framework and championing new methods, including emphasizing the central role that multilevel analysis holds for explicating pathways of risk and resilience. His work continues to change the face of existing science. It has also paved the way for the formation of new projects, like the Research Domain Criteria initiative. This paper uses our laboratory's work on multilevel approaches to studying adolescent depression, non-suicidal self-injury, and suicidal thoughts and behaviors to shine a spotlight on Dr Cicchetti's contributions. In addition, we review recent developments, ongoing challenges, and promising future directions within developmental psychopathology as we endeavor to carry on the tradition of growth in the field.

Background: Adolescence is a critical period for brain development, consolidation of self-understanding, and onset of non-suicidal self-injury (NSSI). This study evaluated the RDoC (Research Domain Criteria) sub-construct of Self-Knowledge in relation to adolescent NSSI using multiple units of analysis., Methods: One hundred and sixty-four adolescents assigned female at birth (AFAB), ages 12-16 years with and without a history of NSSI entered a study involving clinical assessment and magnetic resonance imaging (MRI), including structural, resting-state functional MRI (fMRI), and fMRI during a self-evaluation task. For imaging analyses, we used an a priori defined Self Network (anterior cingulate, orbitofrontal, and posterior cingulate cortices; precuneus). We first examined interrelationships among multi-level Self variables. We then evaluated the individual relationships between NSSI severity and multi-level Self variables (self-report, behavior, multi-modal brain Self Network measures), then conducted model testing and multiple regression to test how Self variables (together) predicted NSSI severity., Results: Cross-correlations revealed key links between self-reported global self-worth and self-evaluation task behavior. Individually, greater NSSI severity correlated with lower global self-worth, more frequent and faster negative self-evaluations, lower anterior Self Network activation during self-evaluation, and lower anterior and posterior Self Network resting-state connectivity. Multiple regression analysis revealed the model including multi-level Self variables explained NSSI better than a covariate-only model; the strongest predictive variables included self-worth, self-evaluation task behavior, and resting-state connectivity., Conclusions: Disruptions in Self-Knowledge across multiple levels of analysis relate to NSSI in adolescents. Findings suggest potential neurobiological treatment targets, potentially enhancing neuroplasticity in Self systems to facilitate greater flexibility (more frequently positive) of self-views in AFAB adolescents.

Engagement in nonsuicidal self-injury (NSSI) often begins in adolescence, and commonly occurs when a person is emotionally dysregulated. Parental emotion socialization (ES) plays a key role in shaping children's emotional expression, experience, and regulation. Longitudinal work is needed to understand how links between parental ES and adolescent clinical outcomes unfold over time. In this longitudinal study (N = 118; all assigned female at birth with a range of NSSI - from none to severe; age 12-17 years, Mage = 14.98 at the first assessment), for the Time 1 (T1) and Time 2 (T2) annual assessments; adolescents reported NSSI and adolescents and parents reported depressive symptoms. Parents (primarily mothers) reported on their supportive and unsupportive ES responses to youth expressions of sadness, anger, and happiness. We examined (1) concurrent relationships across time points, (2) longitudinal models (T1 to T2 change in parental ES and its associated T1 to T2 changes in adolescent clinical outcomes), and (3) prediction models (T1 parental ES predicting changes in adolescent clinical outcomes). Concurrent associations between parental supportive ES responses to sadness and anger were inversely related to adolescent's depressive symptoms and NSSI episodes. Longitudinal analyses showed that increases in unsupportive responses to sadness correspond with increases in depressive symptoms from T1 to T2. The findings underscore the importance of examining how parents respond to their children's emotions. Next steps are to investigate potential mechanisms of risk and consider interventions that enhance adaptive responses of parents to adolescents embroiled in negative emotional states., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Despite preliminary evidence that links impulsivity to suicide risk among Native American youth, impulsivity has not been directly studied in relation to suicide ideation (SI) or behaviors in this population. We examined indexes of rapid-response impulsivity (RRI) across multiple levels of analysis (self-report, behavioral, neurobiological) and associations with SI among Native American youth ages 9-10 in the Adolescent Brain Cognitive Development Study., Methods: Data from the sample (n = 284) included self-report (UPPS-P), behavioral (Stop Signal Task), and neurobiological (right inferior frontal gyrus activation) indicators of RRI. RRI indicators were modeled using variable-centered (i.e., traditional multivariable regression) and person-centered (i.e., clustering analyses) approaches in measuring their association with SI., Results: Logistic regression analysis demonstrated that higher negative urgency was associated with higher odds of SI (Adjusted Odds Ratio = 1.23, p = 0.015). Latent profile analysis clustered youth into five profiles based on within-individual variation in RRI indicators. Youth with an elevated self-reported negative and positive urgency profile had higher odds of reporting SI than "normative" youth (Adjusted Odds Ratio = 2.38, p = 0.019)., Limitations: Limitations of this study include the modest sample size particularly regarding SI (14.1 %), potential bias in estimates of lifetime SI, and generalizability to youth from specific Native American communities., Conclusions: Negative urgency may increase risk for SI among Native American youth in late childhood. Clinical implications, including the potential for person-centered RRI profiles to act as candidate markers of suicide risk and resilience in adolescence and inform safety assessments and planning, are discussed., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Transcranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD., Objective/hypothesis: This pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD., Methods: 15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R)., Results: 14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response., Limitations: Main limitations include a small sample size and open-label design., Conclusions: These findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The contributions of religion to reduced suicide risk have been studied in adults and adolescents, though to our knowledge no comprehensive investigation has been conducted in early adolescents, at a time coinciding with emergence of suicide risk trajectories. In this largest study to date on this topic, we aimed to characterise the contributions of various measures of "private" and "public" religiosity to early adolescent suicide ideation (SI) and suicide attempt (SA) histories using information from a large, epidemiologically informed U.S. sample of adolescents (N = 7068; mean age = 12.89 years, 47% female) and their parents. In all youth, parent-reported adolescent religious importance was associated with reduced odds of SA (OR = 0.75, CI = 0.61-0.92, P = .005). Muslim youth were more likely (OR = 1.52, CI = 1.02-2.22, P = .033), and Catholic youth were less likely (OR = 0.80, CI = 0.67-0.95, P = .014), to report SI. A variety of sex differences were noted, with significant protective associations of adolescent self-reported religiosity on SI and SA, religious service attendance on SI, and religious importance on SI, in female-but not male-youth; and significant protective associations of religious importance on SA in male-but not female-youth. Against expectations, there was no evidence that parent religiosity moderated the link between youth religiosity and SI or SA. These results shed light on the roles of cultural and familial context in youth suicide risk, which may ultimately be targeted in screening and interventional approaches., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The complexity of brain signals may hold clues to understand brain-based disorders. Sample entropy, an index that captures the predictability of a signal, is a promising tool to measure signal complexity. However, measurement of sample entropy from fMRI signals has its challenges, and numerous questions regarding preprocessing and parameter selection require research to advance the potential impact of this method. For one example, entropy may be highly sensitive to the effects of motion, yet standard approaches to addressing motion (e.g., scrubbing) may be unsuitable for entropy measurement. For another, the parameters used to calculate entropy need to be defined by the properties of data being analyzed, an issue that has frequently been ignored in fMRI research. The current work sought to rigorously address these issues and to create methods that could be used to advance this field., Methods: We developed and tested a novel windowing approach to select and concatenate (ignoring connecting volumes) low-motion windows in fMRI data to reduce the impact of motion on sample entropy estimates. We created utilities (implementing autoregressive models and a grid search function) to facilitate selection of the matching length m parameter and the error tolerance r parameter. We developed an approach to apply these methods at every grayordinate of the brain, creating a whole-brain dense entropy map. These methods and tools have been integrated into a publicly available R package ("powseR"). We demonstrate these methods using data from the ABCD study. After applying the windowing procedure to allow sample entropy calculation on the lowest-motion windows from runs 1 and 2 (combined) and those from runs 3 and 4 (combined), we identified the optimal m and r parameters for these data. To confirm the impact of the windowing procedure, we compared entropy values and their relationship with motion when entropy was calculated using the full set of data vs. those calculated using the windowing procedure. We then assessed reproducibility of sample entropy calculations using the windowed procedure by calculating the intraclass correlation between the earlier and later entropy measurements at every grayordinate., Results: When applying these optimized methods to the ABCD data (from the subset of individuals who had enough windows of continuous "usable" volumes), we found that the novel windowing procedure successfully mitigated the large inverse correlation between entropy values and head motion seen when using a standard approach. Furthermore, using the windowed approach, entropy values calculated early in the scan (runs 1 and 2) are largely reproducible when measured later in the scan (runs 3 and 4), although there is some regional variability in reproducibility., Discussion: We developed an optimized approach to measuring sample entropy that addresses concerns about motion and that can be applied across datasets through user-identified adaptations that allow the method to be tailored to the dataset at hand. We offer preliminary results regarding reproducibility. We also include recommendations for fMRI data acquisition to optimize sample entropy measurement and considerations for the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Roediger, Butts, Falke, Fiecas, Klimes-Dougan, Mueller and Cullen.)

Purpose: Young women are typically thought to be protected from cardiovascular disease (CVD) before menopause. However, posttraumatic stress disorder (PTSD) increases CVD risk in women by up to threefold. Data in predominantly male cohorts point to physiological mechanisms such as vascular and autonomic derangements as contributing to increased CVD risk. The purpose of the study reported here was to determine whether young women diagnosed with PTSD, compared to those without, present with arterial stiffness and impaired autonomic control of the heart., Methods: A total of 73 healthy young women, ranging in age from 18 to 40 years, with a history of trauma exposure were included in this study, 32 with and 41 without a clinical PTSD diagnosis. We measured resting pulse wave velocity (PWV), central hemodynamics, augmentation pressure and augmentation index (AI) via pulse wave analysis using applanation tonometry. Heart rate variability was also assessed via peripheral arterial tone., Results: In comparison to controls, women with PTSD showed higher central arterial pressure (mean ± standard deviation: systolic blood pressure 104 ± 8 vs. 97 ± 8 mmHg, p < 0.001; diastolic blood pressure 72 ± 7 vs. 67 ± 7 mmHg, p = 0.003), PWV (6 ± 0.3 vs. 5 ± 0.6 m/s, p < 0.001) and AI (22 ± 13 vs. 15 ± 12%, p = 0.007) but lower standard deviation of normal-to-normal intervals (SDNN; 44 ± 17 vs. 54 ± 18 ms, p = 0.005) and root mean square of successive differences between normal heartbeats (RMSSD; 37 ± 17 vs. 51 ± 22 ms, p = 0.002)., Conclusion: PTSD in young women is associated with higher brachial and central pressures, increased arterial stiffness and blunted parasympathetic control of the heart. These findings illustrate potential mechanisms underlying high risk for CVD in young women with PTSD, suggesting possible treatment targets for this at-risk group., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Preliminary evidence shows that discordance in stress experience, expression, and physiology (EEP) in adolescents is linked to depression, suicidal ideation (SI), non-suicidal self-injury (NSSI), and brain functioning. This study employs person-centered analysis to probe the relationship between stress responses, psychopathology, and neural patterns in female adolescents who are oversampled for engagement in NSSI., Methods: Adolescent females ( N = 109, ages 12-17) underwent a social stress test from which self-report measures of stress experience, observer ratings of stress expression, and physiological metrics of stress (via salivary cortisol) were obtained. Multi-trajectory modeling was employed to identify concordant and discordant stress EEP groups. Depressive symptoms, SI and attempt, NSSI engagement, frontal and limbic activation to emotional stimuli, and resting state fronto-limbic connectivity were examined in the EEP groups derived from the multi-trajectory models., Results: Four groups were identified, three of which demonstrated relatively concordant EEP and one which demonstrated discordant EEP ( High Experience-High Expression-Low Physiology ). Further, replicating past research, the High Experience-High Expression-Low Physiology discordant group exhibited higher depressive symptoms, SI, suicide attempt, and NSSI episodes (only for sensitivity analyses based on past year) relative to other EEP groups. No significant group differences in brain functioning emerged., Conclusion: Results indicate that within-person, multi-level patterns in stress responding capture risk for dysfunction including depression and self-injurious thoughts and behaviors. Further interrogating of system-level stress functioning may better inform assessment and intervention efforts.

Resilience promotes positive adaptation to challenges and may facilitate recovery for adolescents experiencing psychopathology. This work examined concordance across the experience, expression, and physiological response to stress as a protective factor that may predict longitudinal patterns of psychopathology and well-being that mark resilience. Adolescents aged 14-17 at recruitment (oversampled for histories of non-suicidal self-injury; NSSI) were part of a three-wave (T1, T2, T3) longitudinal study. Multi-trajectory modeling produced four distinct profiles of stress experience, expression, and physiology at T1 (High-High-High, Low-Low-Low, High-Low-Moderate, and High-High-Low, respectively). Linear mixed-effect regressions modeled whether the profiles predicted depressive symptoms, suicide ideation, NSSI engagement, positive affect, satisfaction with life, and self-worth over time. Broadly, concordant stress response profiles (Low-Low-Low, High-High-High) were associated with resilient-like patterns of psychopathology and well-being over time. Adolescents with a concordant High-High-High stress response profile showed a trend of greater reduction in depressive symptoms ( B = 0.71, p = 0.052), as well as increased global self-worth ( B = -0.88, p = 0.055), from T2 to T3 compared to the discordant High-High-Low profile. Concordance across multi-level stress responses may be protective and promote future resilience, whereas blunted physiological responses in the presence of high perceived and expressed stress may indicate poorer outcomes over time.

Adolescence is a particularly important period for brain development and is also when mood disorders typically emerge. Several psychiatric illnesses exhibit mitochondrial dysfunction, elevated inflammation, and impaired white matter integrity. This study explored the intersection of mitochondrial health, NLRP3 inflammasome activation, and white matter integrity in a small cohort of 29 adolescent patients with mood disorders (bipolar disorder (BD): n = 11, major depressive disorder (MDD): n = 19) and 19 healthy controls. In this sample, adolescents with mood disorders showed lower fractional anisotropy of the ventral cingulum bundle than healthy controls. Across all adolescents, we demonstrated a significant relationship between mitochondrial electron transport chain gene expression, and NLRP3 inflammasome gene expression and activation. Furthermore, circulating cell free mitochondrial DNA was associated with lower white matter integrity in the anterior thalamic radiation. Exploratory subgroup analyses revealed that adolescents with bipolar disorder exhibited lower levels of mitochondrial gene expression and volume, along with increased sensitivity to NLRP3 inflammasome activation compared to adolescents with unipolar depression. Overall, our results reveal relationships between peripherally-measured endpoints of mitochondrial health and NLRP3 inflammasome activation, and centrally measured endpoints of white matter integrity in adolescents. Together with subtle patterns of aberrant neural and biological structure and function in association with mood disorder diagnoses, these results may shed light on the pathophysiology of disease in this early phase of illness., Competing Interests: Declaration of competing interest The authors declare no conflict of interest with the work in this manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Dysfunction in the hypothalamic-pituitary-adrenal axis has been associated with depressive and anxiety disorders. Little is known about the risk for these disorders among individuals with congenital adrenal hyperplasia (CAH), a form of primary adrenal insufficiency., Objective: We investigated the prevalence of depressive and anxiety disorders and antidepressant prescriptions in two large healthcare databases of insured children, adolescents, and young adults with CAH in the United States., Methods: We conducted a retrospective cohort study using administrative data from October 2015 through December 2019 for individuals aged 4-25 years enrolled in employer-sponsored or Medicaid health plans., Results: Adjusting for age, the prevalence of depressive disorders [adjusted prevalence ratio (aPR) = 1.7, 95% confidence interval (CI): 1.4-2.0, p<0.001], anxiety disorders [aPR = 1.7, 95% CI: 1.4-1.9, p<0.001], and filled antidepressant prescriptions [aPR = 1.7, 95% CI: 1.4-2.0, p<0.001] was higher among privately insured youth with CAH as compared to their non-CAH peers. Prevalence estimates were also higher among publicly insured youth with CAH for depressive disorders [aPR = 2.3, 95% CI: 1.9-2.9, p<0.001], anxiety disorders [aPR = 2.0, 95% CI: 1.6-2.5, p<0.001], and filled antidepressant prescriptions [aPR = 2.5, 95% CI: 1.9-3.1, p<0.001] as compared to their non-CAH peers., Conclusions: The elevated prevalence of depressive and anxiety disorders and antidepressant prescriptions among youth with CAH suggests that screening for symptoms of depression and anxiety among this population might be warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Harasymiw, Grosse, Cullen, Bitsko, Perou and Sarafoglou.)

Objective: Psychiatric disorders commonly emerge prior to adulthood. Identification and intervention may vary significantly across populations. We leveraged a large population-based study to estimate the prevalence of psychiatric disorders and treatments, and evaluate predictors of treatment, in children ages 9-10 in the United States., Method: We analyzed cross-sectional data from the Adolescent Brain Cognitive Developmental (ABCD) Study. The Computerized Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-COMP) was used to estimate clinical diagnoses, and the Child Behavior Checklist (CBCL) was used to assess internalizing and externalizing psychopathology. Parents reported on prescription medications and other mental health interventions. Prevalence rates of KSADS diagnoses and treatments were calculated. Logistic regression analyses estimated associations between clinical and sociodemographic predictors (sex at birth, race, ethnicity, income, education, urbanicity) and treatments., Results: The most common KSADS diagnoses were anxiety disorders, followed by attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder. ADHD and depression diagnoses predicted stimulant and antidepressant medication use, respectively. Bipolar and ADHD diagnoses also predicted antidepressant medications, outpatient treatment and psychotherapy. The odds of reporting specific treatments varied by sex, ethnic and racial identities, urbanicity, and income., Conclusion: Expected rates of KSADS-based psychiatric symptoms are present in the ABCD sample at ages 9-10, with treatment patterns broadly mapping onto psychopathology in expected ways. However, we observed important variations in reported treatment utilization across sociodemographic groups, likely reflecting societal and cultural influences. Findings are considered in the context of potential mental health disparities in U.S. children., Competing Interests: Disclosure: Dr. Fiecas is supported in part by the Masonic Institute for the Developing Brain at the University of Minnesota. Ms. Duffy, Dr. Gandhi, Ms. Falke, Ms. Wiglesworth, Dr. Mueller, Dr. Klimes-Dougan, Dr. Luciana, and Dr. Cullen report no biomedical financial interests or potential conflicts of interest.

Background: Non-suicidal self-injury (NSSI) in adolescence is thought to stem from interactions between vulnerability in developing biological systems and experience of stressors. The current study assesses whether multiple levels of the stress system's response to threat could prospectively predict NSSI engagement during the COVID-19 pandemic, a shared, time-locked stressor., Methods: Participants were 64 female adolescents (ages 12-16) from community and clinical settings who were oversampled for NSSI histories. Prior to the onset of the COVID-19 pandemic, adolescents completed a protocol that measured hypothalamic-pituitary-adrenal axis response to a social stressor (via salivary cortisol), amygdala volume, amygdala emotion-evoked activation, and frontolimbic resting-state functional connectivity. During early months of the pandemic (Summer 2020), measures of NSSI behavior (Inventory of Statements About Self-Injury), emotion regulation difficulties (Difficulties in Emotion Regulation Scale), perceived stress (Perceived Stress Scale), and pandemic-related stressors (Epidemic Pandemic Impacts Inventory) were collected. Multinomial logistic regression was used to assess if pre-pandemic biomarkers predicted mid-pandemic NSSI engagement: persistence of NSSI (Persist; N = 21), cessation of NSSI (Desist; N = 26), and no history of NSSI (Never; N = 17). Linear regressions explored if pre-pandemic biomarkers predicted mid-pandemic difficulties in emotion regulation and perceived stress., Results: Higher pre-pandemic overall cortisol response to stress and amygdala emotion-evoked activation characterized adolescents who persisted in NSSI, compared to those who desisted. These findings remained significant when controlling for pandemic related stressors. Lower prepandemic cortisol reactivity predicted more difficulties in emotion regulation during the pandemic. This finding did not remain significant after controlling for pandemic related stressors., Conclusions: Findings suggest that patterns in key biological threat response systems may confer vulnerability for risk outcomes including NSSI engagement in adolescent females in the context of a shared, novel, naturally-occurring stressor. The results point to the importance of multi-level, longitudinal approaches for understanding the interface between developing neurobiological systems and experiential stress in at-risk adolescents. Identified patterns give insight into potential risk assessment strategies based on an understanding of the multi-level threat response., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to report., (Copyright © 2023. Published by Elsevier Ltd.)

Emerging research suggests suicidality may have increased during the COVID-19 pandemic. This cross-sectional study aimed to advance understanding of suicide risk during the pandemic through novel use of a large insurance database. Using logistic regression across time-points, we estimated the effect of exposure to SARS-CoV-2 infection on rates of suicidal ideation and suicide attempts in infected individuals versus uninfected controls during the pandemic (March 2020 - September 2021). In uninfected individuals, we estimated the effect of exposure to the pandemic period versus the pre-pandemic control period (January 2017 to February 2020) on suicidality rates. We also investigated within-pandemic temporal patterns of suicidality. All patients with data in the UnitedHealth Group claims during those intervals were included. ICD-10 codes defined suicidality measures. There were 525,312,717 (62.3% over age 45, 57.7% female) included encounters. From the pandemic subsample (32.8%), 1.7% were COVID+. Adjusted odds ratios showed that COVID+ patients were significantly more likely to have suicidal ideation and suicide attempts than COVID- patients. Among COVID- patients, adjusted odds of suicidality were significantly lower during versus prior to the pandemic. Results were unfortunately limited by the absence of data on deaths by suicide. Further research should examine how SARS-CoV-2 infection may influence suicidality., (Copyright © 2023. Published by Elsevier B.V.)

Background: Nonsuicidal self-injury (NSSI), a transdiagnostic behavior, often emerges during adolescence. This study used the Research Domain Criteria approach to examine cognitive control (CC) with a focus on response inhibition and urgency relative to NSSI severity in adolescents., Methods: One hundred thirty-eight adolescents, assigned female sex at birth, with a continuum of NSSI severity completed negative and positive urgency measurements (self-report), an emotional Go/NoGo task within negative and positive contexts (behavioral), and structural and functional imaging during resting state and task (brain metrics). Cortical thickness, subcortical volume, resting-state functional connectivity, and task activation focused on an a priori-defined CC network. Eighty-four participants had all these main measures. Correlations and stepwise model selection followed by multiple regression were used to examine the association between NSSI severity and multiunit CC measurements., Results: Higher NSSI severity correlated with higher negative urgency and lower accuracy during positive no-inhibition (Go). Brain NSSI severity correlates varied across modalities and valence. For right medial prefrontal cortex and right caudate, higher NSSI severity correlated with greater negative but lower positive inhibition (NoGo) activation. The opposite pattern was observed for the right dorsolateral prefrontal cortex. Higher NSSI severity correlated with lower left dorsal anterior cingulate cortex (ACC) negative inhibition activation and thicker left dorsal ACC, yet it was correlated with higher right rostral ACC positive inhibition activation and thinner right rostral ACC, as well as lower CC network resting-state functional connectivity., Conclusions: Findings revealed multifaceted signatures of NSSI severity across CC units of analysis, confirming the relevance of this domain in adolescent NSSI and illustrating how multimodal approaches can shed light on psychopathology.

Background: Suicide 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., Methods: Data 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., Results: Children 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., Conclusions: Results 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.

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. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Purpose: 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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023 S. Karger AG, Basel.)

Background: Non-suicidal self-injury (NSSI) is a highly prevalent clinical concern in adolescents and is associated with impaired functioning and suicide risk. The BRIDGES (BRain Imaging Development of Girls' Emotion and Self) study was designed to collect longitudinal clinical and neurobiological data to advance our understanding of NSSI in adolescents. The purpose of this paper is to describe the clinical data collected as part of this study, including psychiatric diagnoses, depression symptoms, episodes of non-suicidal self-injury, suicidal thoughts and behaviors, childhood trauma, and personality domains., Methods: The baseline sample included 164 adolescents aged 12-16 assigned female at birth (Mean age = 14.97, SD = 1.20) with NSSI histories ranging from none to severe. Participants and their parent/guardian were invited to provide data at three time points spaced approximately one year apart. Descriptive analyses were conducted to provide estimates of rates and trajectories of clinical data., Results: Of the 164 study participants, 75.61% and 57.93% completed the second and third time points, respectively. Visual inspection of the data suggests an overall trend of decreasing severity of psychopathology over time, and adolescents with a history of NSSI appeared to have higher rates of psychopathology than those without., Conclusions: This paper describes longitudinal clinical trajectories in adolescents with a range of NSSI histories and presents readers with an overview of the rich, publicly available dataset that we hope will inspire future research to advance the understanding of the neurodevelopmental trajectories associated with NSSI, depression, and suicide risk., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.

Competing Interests: Declaration of Competing Interest No authors have any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three (3) years of beginning the work submitted that could inappropriately influence, or be perceived to influence, their work.

Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving 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. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk., (© 2022. Crown.)

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.

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., (Copyright © 2021. Published by Elsevier B.V.)

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.

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.

Nonsuicidal self-injury (NSSI) is a serious clinical problem, particularly for adolescents and young adults. NSSI is a complex behavior that emerges through the intersecting effects of social, psychological, and biological mechanisms. Although the social and psychological contributions to risk for developing NSSI are relatively well understood and have guided the development of effective psychosocial treatments for self-injury, the biological mechanisms underlying NSSI have just begun to come to light. To evaluate and categorize the biological research conducted on the topic of NSSI, we propose a model that distinguishes between trait and state markers. According to this model, risk factors and mechanisms involved in NSSI can be distinguished into both trait and state factors. We review the existing evidence on distal biological traits (predictors) of NSSI, proximal biological traits (correlates) of NSSI, and biological states directly preceding or following NSSI. We conclude by providing recommendations for future research on the neurobiology of NSSI., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Investigation of brain changes in functional connectivity and functional network topology from receiving 8-week selective serotonin reuptake inhibitor (SSRI) treatments is conducted in 12 unmedicated adolescents with major depressive disorder (MDD) by using wavelet-filtered resting-state functional magnetic resonance imaging (fMRI). Changes are observed in frontal-limbic, temporal, and default mode networks. In particular, topological analysis shows, at the global scale and in the 0.12-0.25 Hz band, that the normalized clustering coefficient and smallworldness of brain networks decreased after treatment. Regional changes in clustering coefficient and efficiency were observed in the bilateral caudal middle frontal gyrus, rostral middle frontal gyrus, superior temporal gyrus, left pars triangularis, putamen, and right superior frontal gyrus. Furthermore, changes of nodal centrality and changes of connectivity associated with these frontal and temporal regions confirm the global topological alternations. Moreover, frequency dependence is observed from FDR-controlled subnetworks for the limbic-cortical connectivity change. In the high-frequency band, the altered connections involve mostly frontal regions, while the altered connections in the low-frequency bands spread to parietal and temporal areas. Due to the limitation of small sample sizes and lack of placebo control, these preliminary findings require confirmation with future work using larger samples. Confirmation of biomarkers associated with treatment could suggest potential avenues for clinical applications such as tracking treatment response and neurobiologically informed treatment optimization.

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., (© 2020. The Author(s).)

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 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). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities 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 clinical value of these brain-PAD estimates., (© 2020. The Author(s).)

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research., (© 2020 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)