Clenbuterol attenuates immune reaction to lipopolysaccharide and its relationship to anhedonia in adolescents.

While inflammation has been implicated in psychopathology, relationships between immune-suppressing processes and psychiatric constructs remain elusive. This study sought to assess whether ß2-agonist clenbuterol (CBL) would attenuate immune activation in adolescents with mood and anxiety symptoms following ex vivo exposure of whole blood to lipopolysaccharide (LPS). Our focus on adolescents aimed to target a critical developmental period when psychiatric conditions often emerge and prior to chronicity effects. To capture a diverse range of immunologic and symptomatologic phenotypes, we included 97 psychotropic-medication free adolescents with mood and anxiety symptoms and 33 healthy controls. All participants had comprehensive evaluations and dimensional assessments of psychiatric symptoms. Fasting whole-blood samples were collected and stimulated with LPS in the presence and absence of CBL for 6 hours, then analyzed for 41 cytokines, chemokines, and hematopoietic growth factors. Comparison analyses used Bonferroni-corrected nonparametric tests. Levels of nine immune biomarkers-including IL-1RA, IL-1ß, IL-6, IP-10, MCP-1, MIP-1α, MIP-1ß, TGF-α, and TNF-α-were significantly reduced by CBL treatment compared to LPS alone. Exploratory factor analysis reduced 41 analytes into 5 immune factors in each experimental condition, and their relationships with psychiatric symptoms were examined as a secondary aim. CBL + LPS Factor 4-comprising EGF, PDGF-AA, PDGF-AB/BB, sCD40L, and GRO-significantly correlated with anticipatory and consummatory anhedonia, even after controlling for depression severity. This study supports the possible inhibitory effect of CBL on immune activation. Using a data-driven method, distinctive relationships between CBL-affected immune biomarkers and dimensional anhedonia were reported, further elucidating the role of ß2-agonism in adolescent affective symptomatology.

Connection During COVID-19: Pilot Study of a Telehealth Group Parenting Intervention.

OBJECTIVE: The COVID-19 pandemic has resulted in considerable stress for families, placing parents at risk for heightened psychological distress, while prompting widespread changes in mental health service delivery. This study evaluated treatment engagement, acceptability, and psychiatric distress among participants in the telehealth adaptation of the Connecting and Reflecting Experience (CARE) program after the onset of COVID-19. METHODS: CARE is a transdiagnostic, bigenerational, mentalizing-focused group parenting intervention based out of an outpatient child mental health clinic in an underserved urban community. Individuals participating in CARE during the clinic's transition to telehealth services were recruited for participation in this pre-post design pilot study. Participants (N=12) completed self-report surveys before and after their first telehealth group session and at their 20-week follow-up. Quantitative and qualitative measures were used to evaluate psychiatric symptoms, treatment engagement, and preliminary acceptability of the adaptation. RESULTS: Self-reported mood and anxiety symptoms decreased significantly after 20 weeks of telehealth therapy. Participants reported high levels of therapeutic alliance and group cohesion in the telehealth format. Results also showed minimal participant-reported privacy concerns and a trend toward increased treatment engagement. CONCLUSIONS: These findings have implications regarding the acceptability of teletherapy interventions for caregivers of children during this period of heightened vulnerability and limited access to social support and health services. They also are relevant to establishing the preliminary acceptability of mentalizing-focused parenting inventions delivered via telehealth.

Detailed mapping of human habenula resting-state functional connectivity.

The habenula (Hb) inhibits dopaminergic reward signaling in response to negative outcomes and has been linked to numerous functional domains relevant to mental health, including reward prediction, motivation, and aversion processing. Despite its important neuroscientific and clinical implications, however, the human Hb remains poorly understood due to its small size and the associated technical hurdles to in vivo functional magnetic resonance imaging (fMRI) investigation. Using high-resolution 3 T fMRI data from 68 healthy young adults acquired through the Human Connectome Project, we developed a rigorous approach for mapping the whole-brain resting-state functional connectivity of the human Hb. Our study combined an optimized strategy for defining subject-level connectivity seeds to maximize Hb blood-oxygen-level-dependent (BOLD) signal sensitivity with high-quality surface-based alignment for robust functional localization and cortical sensitivity. We identified significant positive Hb connectivity with: (i) conserved brainstem targets, including the dopaminergic ventral tegmental area, serotonergic raphe nuclei, and periaqueductal gray; (ii) subcortical structures related to reward and motor function, including the nucleus accumbens, dorsal striatum, pallidum, thalamus, and cerebellum; and (iii) cortical areas associated with the Salience Network and early sensory processing, including the dorsal anterior cingulate, anterior insula, and primary visual and auditory cortices. Hb connectivity was strongly biased towards task-positive brain regions, with weak or negative connectivity observed throughout the task-negative Default Mode Network. Our study provides a detailed characterization of Hb resting-state functional connectivity in healthy young adults, demonstrating both the feasibility and clinical potential of studying the human Hb using high-resolution 3 T fMRI.

Relationships between neural activation during a reward task and peripheral cytokine levels in youth with diverse psychiatric symptoms.

BACKGROUND: Inflammation has been hypothesized to contribute to reward dysfunction across psychiatric conditions, but little is known about this relationship in youth. Therefore, the present study investigated the associations between general and specific markers of inflammation and neural activation during reward processing, including anticipation and attainment, in youth with diverse psychiatric symptoms. METHODS: Forty-six psychotropic medication-free youth with diverse psychiatric symptoms underwent a blood draw to measure 41 cytokines, as well as structural and functional magnetic resonance imaging. The Reward Flanker Task examined neural activation during reward anticipation and attainment. Relationships between inflammation and neural activation were assessed using data reduction techniques across the whole-brain, as well as in specific reward regions of interest (basal ganglia, anterior and mid-cingulate cortex [ACC/MCC]). RESULTS: Whole-brain principal component analyses showed that factor 3 (12 cytokines: FGF-2, Flt3-L, fractalkine, GM-CSF, IFN-α2, IFN-γ, IL-3, IL-4, IL-7, IL-17A, MDC, and VEGF) was negatively correlated with precuneus/posterior cingulate cortex activity during anticipation. Factor 2 (11 cytokines: eotaxin, IL-1α, IL-1Rα, IL-2, IL-5, IL-9, IL-12p40, IL-13, IL-15, MCP-3, and TNF-ß) was negatively correlated with angular gyrus activity during attainment. ROI analyses additionally showed that multiple cytokines were related to activity in the basal ganglia (EGF, FGF-2, Flt-3L, IL-2, IL-13, IL-15, IL-1Rα, MCP-3) and ACC/MCC (Flt-3L) during attainment. C-reactive protein (CRP) was not associated with neural activation. CONCLUSIONS: Investigation of specific markers of immune function showed associations between inflammatory processes and activation of posterior default mode network, prefrontal cortex, and basal ganglia regions during multiple phases of reward processing.

Resting-state functional connectivity of the human habenula in healthy individuals: Associations with subclinical depression.

INTRODUCTION: The habenula (Hb) is postulated to play a critical role in reward and aversion processing across species, including humans, and has been increasingly implicated in depression. However, technical constraints have limited in vivo investigation of the human Hb, and its function remains poorly characterized. We sought to overcome these challenges by examining the whole-brain resting-state functional connectivity of the Hb and its possible relationship to depressive symptomatology using the high-resolution WU-Minn Human Connectome Project (HCP) dataset. METHODS: Anatomical and resting-state functional MRI data from 50 healthy subjects with low or high subclinical depression scores (n = 25 each) were analyzed. Using novel semi-automated segmentation and optimization techniques, we generated individual-specific Hb seeds and calculated whole-brain functional connectivity for the entire cohort and the contrast of high vs. low depression groups. RESULTS: In the entire cohort, the Hb exhibited significant connectivity with key brainstem structures (i.e., ventral tegmental area, substantia nigra, pons) as well as the anterior and posterior cingulate cortices, precuneus, thalamus, and sensorimotor cortex. Multiple regions showed differential Hb connectivity based on subclinical depression scores, including the amygdala, insula, and prefrontal, mid-cingulate, and entorhinal cortices. CONCLUSIONS: Hb connectivity findings converged on areas associated with salience processing, sensorimotor systems, and the default mode network. We also detected substantial Hb-brainstem connectivity, consistent with prior histological and animal research. High and low subclinical depression groups exhibited differences in Hb connectivity with multiple regions previously linked to depression, suggesting the relationship between these structures as a potential target for future research and treatment. Hum Brain Mapp 37:2369-2384, 2016. © 2016 Wiley Periodicals, Inc.

Personality traits as predictors of depression across the lifespan.

BACKGROUND: Depression is a major public health concern. A barrier for research has been the heterogeneous nature of depression, complicated by the categorical diagnosis of depression which is based on a cluster of symptoms, each with its own etiology. To address the multifactorial etiology of depression and its high comorbidity with anxiety, we aimed to examine the relations between personality traits, diverse behavioral, cognitive and physical measures, and depression and anxiety over the lifespan. METHOD: Our sample was drawn from the NKI-RS, a community-based lifespan sample (N = 1494 participants aged 6 to 85). Analyses included multivariate approach and general linear models for group comparisons and dimensional analyses, respectively. A machine learning model was trained to predict depression using many factors including personality traits. RESULTS: Depression and anxiety were both characterized by increased neuroticism and introversion, but did not differ between themselves. Comorbidity had an additive effect on personality vulnerability. Dimensionally, depression was only associated with personality in adolescence, where it was positively correlated with neuroticism, and negatively correlated with extraversion, agreeableness, and conscientiousness. The relationship between anxiety and personality changed over time, with neuroticism and conscientiousness being the most salient traits. Our machine learning model predicted depression with 70 % accuracy with neuroticism and extraversion contributing most. LIMITATIONS: Due to the cross-sectional design, conclusions cannot be drawn about causal relationships between personality and depression. CONCLUSION: These results underscore the impact of personality on depressive disorders and provide novel insights on how personality contributes to depression across the lifespan.

Immune and Neural Response to Acute Social Stress in Adolescent Humans and Rodents.

Studies in adults have linked stress-related activation of the immune system to the manifestation of psychiatric conditions. Using a translational design, this study aimed to examine the impact of social stress on immune activity in adolescents and on neuronal activity in a preclinical mouse model. Participants were 31 adolescents (ages 12-19), including 25 with mood and anxiety symptoms. Whole-blood samples were collected before and after the Trier Social Stress Test (TSST), a stress-inducing public speaking task, then cultured for 6 hours in the presence and absence of the inflammatory endotoxin lipopolysaccharide (LPS). Effects of TSST and LPS on 41 immune biomarkers were examined using repeated-measures analysis of variance. Separately, juvenile (8-week-old) male mice were non-stressed or exposed to reminder social defeat then intraperitoneally injected with saline or LPS (n = 6/group). Brains were perfused and collected for immunohistochemistry and confocal microscopy at 0, 1, 6, and 24 hours post-injection. Activity was determined by the density of cFos-positive neurons in the paraventricular hypothalamus, paraventricular thalamus, and basolateral amygdala, regions known to show sustained activation to immunological challenge. Analyses in the adolescent study indicated a strong effect of LPS but no effects of TSST or TSST×LPS interaction on immune biomarkers. Similarly, reminder social defeat did not induce sustained neuronal activity changes comparable to LPS immunological challenge in juvenile mice. Our convergent findings across species suggest that the acute immune response to stress documented in adults is not present in youth. Thus, aging and chronicity effects may play an important role in the inflammatory response to acute psychosocial stress.

C-Reactive Protein Does Not Predict Future Depression Onset in Adolescents: Preliminary Findings from a Longitudinal Study.

Introduction: Neuroinflammatory processes have been extensively implicated in the underlying neurobiology of numerous neuropsychiatric disorders. Elevated C-reactive protein (CRP), an indicator of nonspecific inflammation commonly utilized in clinical practice, has been associated with depression in adults. In adolescents, our group previously found CRP to be associated with altered neural reward function but not with mood and anxiety symptoms assessed cross-sectionally. We hypothesized that the distinct CRP findings in adolescent versus adult depression may be due to chronicity, with neuroinflammatory effects on psychiatric disorders gradually accumulating over time. Here, we conducted a longitudinal study to evaluate if CRP levels predicted future onset or progression of depression in adolescents. Methods: Participants were 53 adolescents (age = 14.74 ± 1.92 years, 35 female), 40 with psychiatric symptoms and 13 healthy controls. At baseline, participants completed semistructured diagnostic evaluations; dimensional assessments for anxiety, depression, anhedonia, and suicidality severity; and bloodwork to quantify CRP levels. Clinical assessments were repeated at longitudinal follow-up after ∼1.5 years. Spearman's correlation between CRP levels and follow-up symptom severity were controlled for body mass index, age, sex, and follow-up interval and considered significant at the two-tailed, Bonferroni-adjusted p < 0.05 level. Results: After correction for multiple comparisons, no relationships were identified between baseline CRP levels and follow-up symptom severity. Conclusion: CRP levels were not significantly associated with future psychiatric symptoms in adolescents in this preliminary analysis. This may suggest that CRP is not a useful biomarker for adolescent depression and anxiety. However, future longitudinal studies with larger sample sizes and incorporating additional indicators of neuroinflammation are needed.

I am Lifted Above the World: utilizing VR for stress reduction among perinatal women of color.

Background: Perinatal mental health conditions affect 800,000 individuals annually in the United States and are a leading cause of complications in pregnancy and childbirth. However, the impact of these conditions varies across racial and ethnic groups. Portable digital solutions, such as mobile apps, have been developed for maternal mental health, but they often do not adequately cater to the needs of women of color. To ensure the effectiveness and equity of these interventions, it is crucial to consider the unique experiences of perinatal women from diverse racial backgrounds. This qualitative study aims to explore the complex aspects of motherhood, maternal mental well-being, and resilience among perinatal women of color. It also investigates the factors that either hinder or facilitate the use of Virtual Reality (VR) for stress management in this specific demographic. Methods: This research involves two focus groups comprising perinatal women, primarily identifying as Black or Latina, enrolled in the ongoing Nurturing Moms study at the University of Miami Miller School of Medicine. Additionally, feedback is collected from five different participants. The study assesses Nurture VR™, a VR-based program integrating mindfulness techniques, relaxation exercises, and guided imagery for pregnancy and postpartum. Results: Qualitative analysis uncovers five primary themes and 19 sub-themes, addressing the complexities of motherhood, maternal mental health, attitudes towards VR therapy, postpartum care, and the perception of resilience. Participants share challenges related to household management, caregiving, financial stress, breastfeeding, relaxation, sleep, and the significance of social support. Their preferences and reservations regarding VR therapy are also expressed. Conclusion: This study sheds light on the diverse struggles and obstacles faced by women of color during and after pregnancy, with potential repercussions for their mental and sleep health. It underscores the need for mental health screening and analysis of maternal stress-related sleep issues, in addition to the facilitation of social support in maternal health programs. Additionally, it highlights the promise of culturally responsive behavioral treatments, including VR interventions, in offering timely and tailored mental health support to perinatal women, taking into account their intersectional identities.

C-reactive protein does not predict future depression onset in adolescents: preliminary findings from a longitudinal study.

Introduction: Neuroinflammatory processes have been extensively implicated in the underlying neurobiology of numerous neuropsychiatric disorders. Elevated C-reactive protein (CRP), an indicator of non-specific inflammation commonly utilized in clinical practice, has been associated with depression in adults. In adolescents, our group previously found CRP to be associated with altered neural reward function but not with mood and anxiety symptoms assessed cross-sectionally. We hypothesized that the distinct CRP findings in adolescent vs. adult depression may be due to chronicity, with neuroinflammatory effects on psychiatric disorders gradually accumulating over time. Here, we conducted a longitudinal study to evaluate if CRP levels predicted future onset or progression of depression in adolescents. Methods: Participants were 53 adolescents (ages 14.74 ± 1.92, 35 female), 40 with psychiatric symptoms and 13 healthy controls. At baseline, participants completed semi-structured diagnostic evaluations; dimensional assessments for anxiety, depression, anhedonia, and suicidality severity; and bloodwork to quantify CRP levels. Clinical assessments were repeated at longitudinal follow-up after approximately 1.5 years. Spearman's correlation between CRP levels and follow-up symptom severity were controlled for BMI, age, sex, and follow-up interval and considered significant at the two-tailed, Bonferroni-adjusted p < 0.05 level. Results: After correction for multiple comparisons, no relationships were identified between baseline CRP levels and follow-up symptom severity. Conclusion: CRP levels were not significantly associated with future psychiatric symptoms in adolescents in this preliminary analysis. This may suggest that CRP is not a useful biomarker for adolescent depression and anxiety. However, future longitudinal studies with larger sample sizes and incorporating additional indicators of neuroinflammation are needed.

Racial/ethnic discrimination and suicide-related risk in a treatment-seeking group of ethnoracially minoritized adolescents.

INTRODUCTION AND AIMS: Despite growing evidence demonstrating the negative mental health effects of racism-related experiences, racial/ethnic discrimination is seldom examined in youth suicide risk. The present study tested the association between racial/ethnic discrimination and well-supported correlates of suicide-related risk including emotion reactivity and dysregulation, and severity of psychiatric symptoms in a sample of ethnoracially minoritized adolescents receiving outpatient psychiatric services. METHODS: Participants were adolescents (N = 46; 80.4% female; 65.2% Latinx) who ranged in age from 13-20 years old (M=15.42; SD=1.83) recruited from a child outpatient psychiatry clinic in a low-resourced community in Northeast US. Youth completed a clinical interview and a battery of surveys. RESULTS: Findings from separate linear regression models show that increases in frequency of racial/ethnic discrimination were associated with increases in severity of suicidal ideation (SI), independent of emotion reactivity and dysregulation, and symptoms of PTSD and depression. Discriminatory experiences involving personal insults, witnessing family being discriminated, and school-based contexts were uniquely associated with SI. DISCUSSION AND CONCLUSION: Preliminary findings support the association between racial/ethnic discrimination and increased severity of suicide-related risk in ethnoracially minoritized adolescents. Accounting for racial/ethnic discrimination may improve the cultural responsiveness of youth suicide prevention strategies within outpatient psychiatric care.

Racial and Ethnic Disparities in COVID-19-Related Stressor Exposure and Adverse Mental Health Outcomes Among Health Care Workers.

OBJECTIVE: Racial and ethnic disparities in exposure to COVID-19-related stressors, pandemic-related distress, and adverse mental health outcomes were assessed among health care workers in the Bronx, New York, during the first wave of the pandemic. METHODS: The authors analyzed survey data from 992 health care workers using adjusted logistic regression models to assess differential prevalence of outcomes by race/ethnicity and their interactions. RESULTS: Compared with their White colleagues, Latinx, Black, Asian, and multiracial/other health care workers reported significantly higher exposure to multiple COVID-19-related stressors: redeployment, fear of being sick, lack of autonomy at work, and inadequate access to personal protective equipment. Endorsing a greater number of COVID-19-related stressors was associated with pandemic-related distress in all groups and with adverse mental health outcomes in some groups; it was not related to hazardous alcohol use in any of the groups. These associations were not significantly different between racial and ethnic groups. Latinx health care workers had significantly higher probabilities of pandemic-related distress and posttraumatic stress than White colleagues. Despite greater exposure to COVID-19-related stressors, Black, Asian, and multiracial/other health care workers had the same, if not lower, prevalence of adverse mental health outcomes. Conversely, White health care workers had a higher adjusted prevalence of moderate to severe anxiety compared with Asian colleagues and greater hazardous alcohol use compared with all other groups. CONCLUSIONS: Health care workers from racial and ethnic minority groups reported increased exposure to COVID-19-related stressors, suggestive of structural racism in the health care workforce. These results underscore the need for increased support for health care workers and interventions aimed at mitigating disparities in vocational exposure to risk and stress.

Personality characteristics, not clinical symptoms, are associated with anhedonia in a community sample: A preliminary investigation.

Anhedonia is a salient transdiagnostic psychiatric symptom associated with increased illness severity and chronicity. Anhedonia is also present to varying degrees in non-clinical cohorts. Here, we sought to examine factors influencing expression of anhedonia. Participants (N = 335) were recruited through the Nathan Kline Institute-Rockland Sample, an initiative to deeply phenotype a large community sample across the lifespan. Utilizing a data-driven approach, we evaluated associations between anhedonia severity, indexed by Snaith-Hamilton Pleasure Scale (SHAPS), and 20 physical, developmental, and clinical measures, including Structured Clinical Interview for DSM-IV, Beck Depression Inventory, State-Trait Anxiety Inventory, NEO Five-Factor Inventory-3 (NEO-FFI-3), BMI, Hemoglobin A1C, and demography. Using a bootstrapped AIC-based backward selection algorithm, seven variables were retained in the final model: NEO-FFI-3 agreeableness, extraversion, and openness to experience; BMI; sex; ethnicity; and race. Though median SHAPS scores were greater in participants with psychiatric diagnoses (18.5) than those without (17.0) (U = 12238.5, z = 2.473, p = 0.013), diagnosis and symptom measures were not retained as significant predictors in the final robust linear model. Participants scoring higher on agreeableness, extraversion, and openness to experience reported significantly lower anhedonia. These results demonstrate personality as a mild-to-moderate but significant driver of differences in experiencing pleasure in a community sample.

Multicenter Study of Utility and Acceptability of Depression and Anxiety Screening in Adolescents and Young Adults With Childhood-Onset Systemic Lupus.

OBJECTIVE: To determine the utility and acceptability for depression and anxiety screening of adolescents and young adults (AYA) with childhood-onset systemic lupus erythematosus (cSLE) in the pediatric rheumatology setting. METHODS: AYA with cSLE, ages 12-21 years, from 8 collaborating sites, were consecutively screened for depression and anxiety with the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item scale (GAD-7). Demographic and disease characteristics were collected, as well as patient-reported outcome measures using the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric profile-25. Acceptability of screening was assessed with postscreening surveys completed by AYA and parents. Chi-square and Wilcoxon rank sum tests examined the relationship between patient characteristics and history of previous screening. Spearman correlations examined relationships between screening scores, PROMIS domains, and other disease factors. RESULTS: Among 106 AYA screened, 64 (60%) had been previously screened, 25 (24%) by general pediatricians. Thirty-two (30%) AYA screened positive, including 24% for depression, 17% for anxiety, and 14% for suicidal ideation. Depression and anxiety symptom severity were highly correlated with increased PROMIS domain scores for fatigue and pain interference and moderately correlated with increased pain severity, decreased mobility, and decreased peer relationships. Eighty-six percent of AYA and 95% of parents expressed comfort with screening in the pediatric rheumatology setting. CONCLUSION: Depression, anxiety, and suicidal ideation are common among AYA with cSLE, and symptoms are correlated with important patient-reported outcomes. Mental health screening in the pediatric rheumatology setting was highly acceptable among AYA with cSLE and their parents.

Therapeutic trials for long COVID-19: A call to action from the interventions taskforce of the RECOVER initiative.

Although most individuals recover from acute SARS-CoV-2 infection, a significant number continue to suffer from Post-Acute Sequelae of SARS-CoV-2 (PASC), including the unexplained symptoms that are frequently referred to as long COVID, which could last for weeks, months, or even years after the acute phase of illness. The National Institutes of Health is currently funding large multi-center research programs as part of its Researching COVID to Enhance Recover (RECOVER) initiative to understand why some individuals do not recover fully from COVID-19. Several ongoing pathobiology studies have provided clues to potential mechanisms contributing to this condition. These include persistence of SARS-CoV-2 antigen and/or genetic material, immune dysregulation, reactivation of other latent viral infections, microvascular dysfunction, and gut dysbiosis, among others. Although our understanding of the causes of long COVID remains incomplete, these early pathophysiologic studies suggest biological pathways that could be targeted in therapeutic trials that aim to ameliorate symptoms. Repurposed medicines and novel therapeutics deserve formal testing in clinical trial settings prior to adoption. While we endorse clinical trials, especially those that prioritize inclusion of the diverse populations most affected by COVID-19 and long COVID, we discourage off-label experimentation in uncontrolled and/or unsupervised settings. Here, we review ongoing, planned, and potential future therapeutic interventions for long COVID based on the current understanding of the pathobiological processes underlying this condition. We focus on clinical, pharmacological, and feasibility data, with the goal of informing future interventional research studies.

The possible role of the kynurenine pathway in anhedonia in adolescents.

To address the heterogeneous nature of adolescent major depression (MDD), we investigated anhedonia, a core symptom of MDD. We recently reported activation of the kynurenine pathway (KP), a central neuroimmunological pathway which metabolizes tryptophan (TRP) into kynurenine (KYN) en route to several neurotoxins, in a group of highly anhedonic MDD adolescents. In this study, we aimed to extend our prior work and examine the relationship between KP activity and anhedonia, measured quantitatively, in a group of MDD adolescents and in a combined group of MDD and healthy control adolescents. Thirty-six adolescents with MDD (22 medication-free) and 20 controls were included in the analysis. Anhedonia scores were generated based on clinician- and subject-rated assessments and a semi-structured clinician interview. Blood KP metabolites, collected in the AM after an overnight fast, were measured using high-performance liquid chromatography. The rate-limiting enzyme of the KP, indoleamine 2,3-dioxygenase (IDO), was estimated by the ratio of KYN/TRP. Pearson correlation tests were used to assess correlations between anhedonia scores and KP measures while controlling for MDD severity. IDO activity and anhedonia scores were positively correlated in the group psychotropic medication-free adolescents with MDD (r = 0.42, P = 0.05) and in a combined group of MDD subjects and healthy controls (including medicated patients: r = 0.30, P = 0.02; excluding medicated patients: r = 0.44, P = 0.004). In conclusions, our findings provide further support for the role for the KP, particularly IDO, in anhedonia in adolescent MDD. These results emphasize the importance of dimensional approaches in the investigation of psychiatric disorders.

Allopregnanolone: The missing link to explain the effects of stress on tic exacerbation?

The neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and anti-inflammatory functions to the regulation of mood and emotional responses. Several lines of research show that the brain rapidly produces AP in response to acute stress to reduce the allostatic load and enhance coping. These effects not only are likely mediated by GABAA receptor activation but also result from the contributions of other mechanisms, such as the stimulation of membrane progesterone receptors. In keeping with this evidence, AP has been shown to exert rapid, potent antidepressant properties and has been recently approved for the therapy of moderate-to-severe postpartum depression. In addition to depression, emerging evidence points to the potential of AP as a therapy for other neuropsychiatric disorders, including anxiety, seizures, post-traumatic stress disorder and cognitive problems. Although this evidence has spurred interest in further therapeutic applications of AP, some investigations suggest that this neurosteroid may also be associated with adverse events in specific disorders. For example, our group has recently documented that AP increases tic-like manifestations in several animal models of tic disorders; furthermore, our results indicate that inhibiting AP synthesis and signalling reduces the exacerbation of tic severity associated with acute stress. Although the specific mechanisms of these effects remain partially elusive, our findings point to the possibility that the GABAergic activation by AP may also lead to disinhibitory effects, which could interfere with the ability of patients to suppress their tics. Future studies will be necessary to verify whether these mechanisms may apply to other externalising manifestations, such as impulse-control problems and manic symptoms.

Mental Health Disparities Among Sexual and Gender Minority Frontline Health Care Workers During the Height of the COVID-19 Pandemic.

Purpose: This study measured mental health disparities in a Bronx, New York sample of frontline health care workers collected May-July, 2020, during the first wave of the COVID-19 pandemic. Methods: Using survey data (N = 741), we compared demographics, COVID-19 stressors, and adverse mental health outcomes between sexual and gender minority (SGM, n = 102) and non-SGM (n = 639) health care workers through chi-square/Kruskal-Wallis tests, crude/adjusted odds, and prevalence ratios. Results: SGM frontline health care workers had significantly higher depression, anxiety, impact of COVID-19, and psychological distress. Income (lower), age (younger), and COVID-19 stressors accelerated differences. Conclusion: Health care systems should support SGM frontline health care workers through affirming trauma-informed programming.

Neural function underlying reward expectancy and attainment in adolescents with diverse psychiatric symptoms.

Reward dysfunction has been hypothesized to play a key role in the development of psychiatric conditions during adolescence. To help capture the complexity of reward function in youth, we used the Reward Flanker fMRI Task, which enabled us to examine neural activity during expectancy and attainment of both certain and uncertain rewards. Participants were 84 psychotropic-medication-free adolescents, including 67 with diverse psychiatric conditions and 17 healthy controls. Functional MRI used high-resolution acquisition and high-fidelity processing techniques modeled after the Human Connectome Project. Analyses examined neural activation during reward expectancy and attainment, and their associations with clinical measures of depression, anxiety, and anhedonia severity, with results controlled for family-wise errors using non-parametric permutation tests. As anticipated, reward expectancy activated regions within the fronto-striatal reward network, thalamus, occipital lobe, superior parietal lobule, temporoparietal junction, and cerebellum. Unexpectedly, however, reward attainment was marked by widespread deactivation in many of these same regions, which we further explored using cosine similarity analysis. Across all subjects, striatum and thalamus activation during reward expectancy negatively correlated with anxiety severity, while activation in numerous cortical and subcortical regions during reward attainment positively correlated with both anxiety and depression severity. These findings highlight the complexity and dynamic nature of neural reward processing in youth.

A longitudinal resource for studying connectome development and its psychiatric associations during childhood.

Most psychiatric disorders are chronic, associated with high levels of disability and distress, and present during pediatric development. Scientific innovation increasingly allows researchers to probe brain-behavior relationships in the developing human. As a result, ambitions to (1) establish normative pediatric brain development trajectories akin to growth curves, (2) characterize reliable metrics for distinguishing illness, and (3) develop clinically useful tools to assist in the diagnosis and management of mental health and learning disorders have gained significant momentum. To this end, the NKI-Rockland Sample initiative was created to probe lifespan development as a large-scale multimodal dataset. The NKI-Rockland Sample Longitudinal Discovery of Brain Development Trajectories substudy (N = 369) is a 24- to 30-month multi-cohort longitudinal pediatric investigation (ages 6.0-17.0 at enrollment) carried out in a community-ascertained sample. Data include psychiatric diagnostic, medical, behavioral, and cognitive phenotyping, as well as multimodal brain imaging (resting fMRI, diffusion MRI, morphometric MRI, arterial spin labeling), genetics, and actigraphy. Herein, we present the rationale, design, and implementation of the Longitudinal Discovery of Brain Development Trajectories protocol.