Higher arterial stiffness and blunted vagal control of the heart in young women with compared to without a clinical diagnosis of PTSD.

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.

Revisiting Associations Among Parent and Adolescent Religiosity and Early Adolescent Suicide Risk in the United States.

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.

Brain signatures in children who contemplate suicide: learning from the large-scale ABCD study.

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.

Patterns of experience, expression, and physiology of stress relate to depressive symptoms and self-injurious thoughts and behaviors in adolescents: a person-centered approach.

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.

Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.

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.

Stress system concordance as a predictor of longitudinal patterns of resilience in adolescence.

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.

Behavioral Apophenia and Dimensions of Psychoticism in Adolescents with and without Mood Disorders.

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.

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

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.

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders : Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group.

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.

White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group.

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Multimodal assessment of sustained threat in adolescents with nonsuicidal self-injury.

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.

Characterizing the NLRP3 Inflammasome in Mood Disorders: Overview, Technical Development, and Measures of Peripheral Activation in Adolescent Patients.

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.

Transcendental meditation and hypothalamic-pituitary-adrenal axis functioning: a pilot, randomized controlled trial with young adults.

Transcendental meditation (TM) is effective in alleviating stress and anxiety and promoting well-being. While the underlying biological mechanisms of TM are not yet fully explored, the hypothalamic-pituitary-adrenal (HPA) axis represents an index providing important clues embodying the stress system cascade. In this pilot study, young adults were randomly assigned to TM training followed by 8 weeks of meditation practice or a wait-list control condition. TM was conducted over 8 weeks. Thirty-four young adult participants were randomized; 27 participants completed the HPA outcome assessments (41% male). To assess HPA axis functioning, salivary samples to assess cortisol awakening response (CAR) that were collected in the morning, both at baseline and at week-4. Salivary cortisol in the context of a social stressor using the Trier Social Stress Test (TSST) was collected at week-8. The results indicate that participants who were randomly assigned to TM had lower awakening salivary cortisol levels and a greater drop in CAR from baseline to week-4 than the control group. There were no significant differences in HPA axis functioning in the context of the TSST. Primary limitations of this randomized controlled trial were the small sample size, the use of a wait-list as opposed to an active control, and the limited scope of HPA axis assessments. The results of this pilot study provide tentative evidence that TM may impact biological stress system functioning and suggests that this may be a worthwhile avenue to continue to examine. It will also be useful to extend these findings to a broader array of meditative and mindful practices, particularly for those who are experiencing more distress.

Resting state functional connectivity of networks associated with reward and habit in anorexia nervosa.

Neurobiological disturbances associated with reward and/or habit learning are theorized to maintain symptoms of anorexia nervosa (AN). Although research has investigated responses in brain regions associated with reward and habit to disorder-specific cues (e.g., food) and presumed rewards (e.g., money), little is known about the functional organization of the circuits underlying these constructs independent of stimulus. This study aimed to provide initial data on the synchrony of networks associated with reward and habit in AN by comparing resting-state functional connectivity (RSFC) patterns between AN and healthy control (HC) participants in these circuits and delineating how these patterns relate to symptoms. Using theoretically selected seeds in the nucleus accumbens (NAcc), ventral caudate, and dorsal caudate, reflecting a continuum from reward- to habit- oriented regions, RSFC patterns were compared between AN restricting subtype (n = 19) and HC (n = 19) participants (cluster threshold: p < .01). Exploratory correlations between RSFC z-scores and Eating Disorder Examination (EDE) scores, BMI, and illness duration were conducted. The AN group demonstrated lower RSFC between the NAcc and superior frontal gyrus, between the ventral caudate and frontal and posterior regions, and between the dorsal caudate and frontal, temporal, and posterior regions. In the AN group, lower NAcc- superior frontal gyrus RSFC correlated with greater EDE Global scores (r = -.58, CI: -.83, -.13). These resting-state synchrony disruptions of the ventral and dorsal frontostriatal circuits, considered in context of the broader literature, support the utility of further investigating possible reward and habit disturbances supporting symptoms in AN.

A Pilot Study of Stress System Activation in Children Enrolled in a Targeted Prevention Program: Implications for Personalization.

Empirically validated interventions addressing childhood psychological problems are now readily available, but success likely depends in part on accurately identifying which children will benefit from which intervention. This pilot study examined the stress activation and response system, first as a way to differentiate high versus low-risk children, and second to explore indicators of the stress system associated with favorable intervention response. METHOD: Participants (N = 43, 58% male) were school-aged children who qualified for inclusion in the Early Risers "Skills for Success" Prevention Program based on their elevated levels of aggressive and/or socially withdrawn behavior and a normally developing comparison group. Compared to the normally developing group, children who were participants in the intervention exhibited a more blunted cortisol response to the stress paradigm. However, for the children in the intervention group, elevated cortisol levels at the start of the stress paradigm were concurrently associated with internalizing problems and predictive of improvement in internalizing problems over time. These findings provide preliminary evidence that hypothalamic pituitary adrenal (HPA) axis biological variables may be helpful tools for identifying children who would benefit from intervention and personalizing interventions.

Cortisol Awakening Response, Internalizing Symptoms, and Life Satisfaction in Emerging Adults.

The cortisol awakening response (CAR) has been associated with depression and a broader range of internalizing problems. Emerging adulthood is characterized by numerous stressful transitional life events. Furthermore, the functioning of the neurobiological stress system changes across development. These considerations underscore the importance of evaluating the physiological stress system in emerging adults in identifying the extent to which cortisol levels vary with risk and protective factors for mental health. The present study evaluated the association between internalizing symptoms and perceived life satisfaction with CAR in 32 young adults. Three saliva samples were collected to measure cortisol levels upon awakening and participants completed the Depression Anxiety Stress Scale (DASS) and Satisfaction with Life Scale (SWLS). Results show a significant positive correlation between area under the curve for CAR with internalizing symptoms (DASS total) and the DASS-depression subscale, but not with life satisfaction. Study limitations, implications, and future directions for these finding were discussed.

Executive Attention Impairment in Adolescents With Major Depressive Disorder.

Neural network models that guide neuropsychological assessment practices are increasingly used to explicate depression, though a paucity of work has focused on regulatory systems that are under development in adolescence. The purpose of this study was to evaluate subsystems of attention related to executive functioning including alerting, orienting, and executive attention networks, as well as sustained attention with varying working memory load, in a sample of depressed and well adolescents. Neuropsychological functioning in 99 adolescents diagnosed with major depressive disorder (MDD) and 63 adolescent healthy controls (M = 16.6 years old) was assessed on the Attention Network Test (ANT) and the Continuous Performance Test, Identical Pairs. Adolescents with MDD, particularly those who were not medicated, were slower to process conflict (slower reaction time on the Executive Attention scale of the ANT) compared to controls, particularly for those who were not undergoing psychopharmacological treatment. Tentative evidence also suggests that within the MDD group, orienting performance was more impaired in those with a history of comorbid substance use disorder, and alerting was more impaired in those with a history of a suicide attempt. Adolescents with depression showed impaired executive attention, although cognitive performance varied across subgroups of patients. These findings highlight the importance of examining neurocognitive correlates associated with features of depression and suggest an avenue for future research to help guide the development of interventions.

Multilevel assessment of the neurobiological threat system in depressed adolescents: interplay between the limbic system and hypothalamic-pituitary-adrenal axis.

Integrative, multilevel approaches investigating neurobiological systems relevant to threat detection promise to advance understanding of the pathophysiology of major depressive disorder (MDD). In this study we considered key neuronal and hormonal systems in adolescents with MDD and healthy controls (HC). The goals of this study were to identify group differences and to examine the association of neuronal and hormonal systems. MDD and HC adolescents (N = 79) aged 12-19 years were enrolled. Key brain measures included amygdala volume and amygdala activation to an emotion face-viewing task. Key hormone measures included cortisol levels during a social stress task and during the brain scan. MDD and HC adolescents showed group differences on amygdala functioning and patterns of cortisol levels. Amygdala activation in response to emotional stimuli was positively associated with cortisol responses. In addition, amygdala volume was correlated with cortisol responses, but the pattern differed in depressed versus healthy adolescents, most notably for unmedicated MDD adolescents. The findings highlight the value of using multilevel assessment strategies to enhance understanding of pathophysiology of adolescent MDD, particularly regarding how closely related biological threat systems function together while undergoing significant developmental shifts.

Editorial: Bringing Parenting Into Focus: A Decade of Longitudinal Follow-Up Reveals Potential Parenting Targets for Early Intervention for Adolescent Self-Injury.

The mounting prevalence in adolescents of non-suicidal self-injury (NSSI),1 a behavior known to predict future suicide attempts,2 highlights a critical need for research that can help us understand and prevent it. Research studying the childhood roots of this behavior has the potential to provide the groundwork needed to identify possible avenues for intervention.