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To provide a detailed description of the sonographic appearance and development of various fetal structures of the midbrain and hindbrain (MBHB) during the early second trimester, and to evaluate the impact of the frequency of the transvaginal sonography (TVS) transducer on the early recognition of these structures.This was a retrospective analysis of three-dimensional volumetric datasets of the MBHB from apparently normal fetuses at 14-19 gestational weeks, acquired by TVS in the midsagittal view through the posterior fontanelle. Using a multiplanar approach, we measured the tectal thickness and length, aqueductal thickness, tegmental thickness and width and height of the Blake's pouch (BP) neck. In addition, we assessed the existence of early vermian fissures, the linear shape of the brainstem and the components of the fastigium. The correlation between gestational age according to last menstrual period and sonographic measurements of MBHB structures was evaluated using Pearson's correlation (r). A subanalysis was performed to assess the performance of a 5-9-MHz vs a 6-12-MHz TVS transducer in visualizing the MBHB structures in the early second trimester.Sixty brain volumes were included in the study, obtained at a mean gestational age of 16.2 weeks (range, 14.1-19.0 weeks), with a transverse cerebellar diameter range of 13.0-19.8 mm. We found a strong correlation between gestational age and all MBHB measurements, with the exception of the tectal, tegmental and aqueductal thicknesses, for which the correlation was moderate. There was good-to-excellent intraobserver and moderate-to-good interobserver correlation for most MBHB measurements. We observed that the BP neck was patent in all fetuses between 14 and 18 weeks with decreasing diameter, and that the aqueductal thickness was significantly smaller at ≥ 18 weeks compared with at 16 weeks. The early vermian fissures and the linear shape of the brainstem were present in all fetuses from 14 weeks. We found that, in the early second trimester, the horizontal arm of the presumed 'fastigium' evolves from the fourth ventricular choroid plexus and not the posterior vermis, indicating that this is not the fastigium. Standard- and high-resolution TVS transducers performed similarly in the assessment of MBHB anatomy.Detailed early second-trimester assessment of the MBHB is feasible by transvaginal neurosonography and provides reference data which may help in the early detection of brain pathology involving the MBHB. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Acute stress during pregnancy can have adverse effects on maternal health and increase the risk for postpartum depression and impaired mother-infant bonding. The COVID-19 pandemic represents an acute environmental stressor during which it is possible to explore risk and resilience factors that contribute to postpartum outcomes. To investigate prenatal risk and resilience factors as predictors of postpartum depression and impaired mother-infant bonding, this study recruited a diverse cohort of 833 pregnant women from an urban medical center in Philadelphia, Pennsylvania, and assessed them once during pregnancy in the early phase of the COVID-19 pandemic (April-July 2020) and again at approximately twelve weeks postpartum. Adverse childhood experiences, prenatal depression and anxiety, and COVID-19-related distress predicted a greater likelihood of postpartum depression. Prenatal depression was the only unique predictor of impaired maternal-infant bonding after postpartum depression was controlled for. Women reporting greater emotion regulation, self-reliance, and nonhostile relationships had healthier postpartum outcomes. Policies to increase the number of nonspecialty providers providing perinatal mental health services as well as reimbursement for integrated care and access to mental health screening and care are needed to improve lifelong outcomes for women and their children.

Background COVID-19 pandemic has major ramifications for global health and economy, with growing concerns about economic recession and implications for mental health. Here we investigated the associations between pandemic-related income loss with financial strain and mental health trajectories over a 1-month course, in two independent cohorts. Methods Two independent studies were conducted in the U.S and in Israel at the beginning of the outbreak (March-April 2020, T1; study I: N = 2904, study II: N = 1267) and at a 1-month follow-up (T2; study I: N = 1318, study II: N = 241). Mixed-effects models were applied to assess associations among COVID-19-related income loss, financial strain, and pandemic-related worries about health, with anxiety and depression, controlling for multiple covariates including pre-COVID-19 income. Results In both studies, income loss and financial strain were associated with greater depressive symptoms at T1, above and beyond T1 anxiety, worries about health, and pre-COVID-19 income. Worsening of income loss was associated with exacerbation of depression at T2 in both studies. Worsening of subjective financial strain was associated with exacerbation of depression at T2 in one study (US). Conclusions Income loss and financial strain were uniquely associated with depressive symptoms and their exacerbation over time, above and beyond pandemic-related anxiety. In times when a myriad of stressors are affecting mental health worldwide, our findings reveal specific links between the economic impact of COVID-19 and psychiatric outcomes.

Background Traumatic stressful events (TSEs) are among the most studied risk factors for subsequent schizotypal symptoms. However, specificity and aggregate effects of trauma exposure on schizotypal symptoms remain unclear. This study investigates these relationships among a community-based sample of US adolescents. Material and methods A sub-sample of 426 adolescents (51.6% female) from the Philadelphia Neurodevelopmental Cohort study were selected for longitudinal follow-up based on presence (n = 209) or absence (n = 217) of psychosis spectrum symptoms (PSS). At baseline, they completed assessments of demographic, TSEs, other psychopathology (e.g., PSS, anxiety, depression, and behavioral disorder) and family history of psychopathology. Schizotypal symptom dimensions (cognitive-perceptual, interpersonal and disorganized) were evaluated approximately two years later. Results More than half of adolescents experienced at least one type of TSE. Adolescents with assaultive trauma reported about 1.5 times as many symptoms on all three schizotypal symptom dimensions, compared to adolescents with non-assaultive TSE, adjusting for demographic and family history variables. No statistical significance was found after further adjusting for other baseline psychopathology (p > 0.05). There was a significant aggregate effect of TSEs on cognitive-perceptual symptoms with small effect size (p Conclusions We found evidence of an association between aggregate TSEs and cognitive-perceptual symptoms, but trauma type was not associated with schizotypal symptom dimensions when controlling for potential confounders. Our findings highlight the importance of considering aggregate TSE effects and potential confounds when examining associations between TSEs and schizotypy. Trauma and psychosis spectrum screening may be important in the effort to provide trauma-informed care.

OBJECTIVES To provide evidence to support the hypothesis that the midline cyst-like fluid collection that is frequently observed on fetal brain ultrasound (US) imaging during the early second trimester represents a normal transient cavum veli interpositi (CVI). METHODS This was a retrospective analysis of 89 three-dimensional normal fetal brain volumes, acquired by transvaginal US imaging in 87 pregnant women between 14 and 17 gestational weeks. The midsagittal view was studied using multiplanar imaging, and the maximum length of the fluid collection located over (dorsal to) the tela choroidea of the third ventricle was measured. We calculated the correlation of the transverse cerebellar diameter (TCD) and of the maximum length of the fluid collection with gestational age according to last menstrual period. Color Doppler images were analyzed to determine the location of the internal cerebral veins with respect to the location of the fluid collection. Reports of the second-trimester anatomy scan at 22-24 weeks were also reviewed. RESULTS Interhemispheric fluid collections of various sizes were found in 55% (49/89) of the volumes (mean length, 5 (range, 3.0-7.8) mm). There was a strong correlation between TCD and gestational age (Pearson's correlation, 0.862; P

Objective: Use of risperidone in preschool-aged children is growing, with rising concerns of adverse metabolic consequences. Longitudinal data on risperidone-related weight gain in preschoolers are scarce. We aimed to evaluate changes in body mass index (BMI) that are associated with risperidone treatment in preschoolers. Method: We analyzed naturalistic, longitudinal data on 141 preschool children (112 boys, 29 girls) receiving psychiatric care. Mean patient age at baseline was 5.0 years (SD=0.8) and average follow-up period was 1.3 years (SD=0.8), with >8 mean BMI measurements per patient. We studied the effect of risperidone exposure ( n=78) on age-and-sex-standardized BMI (BMI Z-score) implementing mixed models with random subject intercepts to account for repeated measures, covarying for multiple confounders including demographics, stimulant treatment and psychiatric diagnoses. We employed similar models to study dose and duration effects. Results: Risperidone treatment was significantly associated with an increase in BMI (effect size of exposure=0.45 SD (SE=0.06), t (949)=7.7, pConclusion: Similar to older populations, risperidone treatment in preschoolers is associated with significant weight gain, with evidence for dose effects. Findings provide critical data that can inform clinicians.

OBJECTIVE: Deliberate self-harm (DSH) is a major health concern among adolescents, and is often associated with the need for inpatient psychiatric hospitalization. The aim of this study was to identify clinical and demographic characteristics associated with DSH behavior among adolescents admitted to an acute psychiatric inpatient unit. METHOD: We retrospectively analyzed data from the electronic medical records of consecutive admittances to a single acute adolescent inpatient unit (N=703, mean age 15.2). We compared inpatients with DSH to inpatients without DSH, and further compared within DSH group based on the presence of suicidal intent. RESULTS: Compared to Non-DSH inpatients (N=497), youths admitted following DSH (N=206) were more likely to be female (OR=2.6, 95%CI 1.7–4), currently in depressive exacerbation (OR=2.4, 95%CI 1.6–3.6), with concurrent suicidal ideation (OR=3.9, 95%CI 2.5–5.9), and history of alcohol use (OR=5.6, 95%CI 3.2–9.5). Within DSH youths, no significant clinical differences were identified between those admitted following suicide attempt (N=102) compared to non-suicidal-self-injury (N=104), who were generally younger. CONCLUSIONS: Findings suggest that early detection and intervention of DSH and depressive crisis is warranted, regardless of the self-harm subtype.

Understanding biological mechanisms underlying traumatic stress resilience is critical and can advance preventive psychiatry. Brain phenotypes of stress resilience have been investigated in animals, but such data in humans is scarce. Here we characterize cross-sectional brain correlates of traumatic stress resilience and susceptibility to mood and anxiety psychopathology (MAP) in community youth with substantial trauma exposure. Philadelphia Neurodevelopmental Cohort youths with high-quality structural neuroimaging data were included (N = 1392, mean age ~ 15). MAP was quantified using a dimensional factor score. Resilience and susceptibility were ascertained retrospectively and defined as low/high MAP (respectively) in relation to trauma exposure. This resilience-susceptibility construct was operationalized as the interaction term between trauma exposure and MAP. Clinical functioning level was quantified with the Children Global Assessment Scale. Statistical models examined association of volume, cortical thickness, and gray matter density with resilience, covarying for age, sex, race, socioeconomic status, and image quality. Resilience was associated with better clinical functioning and with specific neural correlates, such that in extensive traumatic stress exposure, smaller brain volume was associated with low MAP; while in low trauma exposure, smaller volumes were correlated with higher MAP. This pattern was evident in total brain volume (trauma by MAP interaction, F(1, 1383), p

Background Anxiety symptoms are common in adolescence and are often considered developmentally benign. Yet for some, anxiety presents with serious comorbid nonanxiety psychopathology. Early identification of such "malignant" anxiety presentations is a major challenge. We aimed to characterize anxiety symptoms suggestive of risk for depression and suicidal ideation (SI) in community youths. Methods Cross-sectional associations were evaluated in community youths (n = 7,054, mean age: 15.8) who were assessed for anxiety, depression, and SI. We employed factor and latent class analyses to identify anxiety clusters and subtypes. Longitudinal risk of anxiety was evaluated in a subset of 330 youths with longitudinal data on depression and SI (with baseline mean age of 12.3 years and follow-up mean age of 16.98 years). Outcomes Almost all (92%) adolescents reported anxiety symptoms. Data-driven approaches revealed anxiety factors and subtypes that were differentially associated with depression and SI. Cross-sectional analyses revealed that panic and generalized anxiety symptoms show the most robust associations with depression and SI. Longitudinal, multivariate analyses revealed that panic symptoms during early adolescence, not generalized anxiety symptoms, predict depression and SI for later adolescent years, particularly in males. Interpretation Anxiety is common in youths, with certain symptom clusters/subtypes predicting risk for depression and SI. Panic symptoms in early adolescence, even below disorder threshold, predict high risk for late adolescent depression and SI.

Objective To provide an in-vivo description of early corpus callosum (CC) development. Methods We reviewed 3D US volumes acquired transvaginally (TVUS) through the anterior fontanelle, between 14 to 17 weeks. The following landmarks were recognized: tela-choroidea (TC), foramina of Moro, early CC and the evolving cavum septi pellucidi. The following measurements were taken: total, anterior and posterior sections, and height of the CC (referenced to the anterior TC border). All measurements were correlated to both the gestational age and the transverse cerebellar diameter (TCD). Results Eighty nine volumes were included in the study (mean 15.1 weeks ± 0.84, TCD range, 13.1-18.4 mm) with high inter and intra observer correlation of the measurements. We found high correlation between CC length and height, and TCD. The anterior segment of the CC appear earlier than the posterior one, and growth continues bi-directionally. Initially, the posterior elongation is significantly larger than the anterior one. Association of all CC measurements with TCD remained significant when co-varying for maternal age and fetal sex. Conclusions imaging the fetal CC is feasible from 14 weeks by TVUS, by following the suggested insonation approach. The early CC develops bi-directionally, and the posterior elongation is more significant than the anterior one.

BackgroundSuicidal thoughts and behavior (STB) in children are a growing health concern, and more data is needed regarding their biological underpinnings. Immune processes such as inflammation have been associated with STB, primarily in adults. Asthma is a common chronic inflammatory disorder in children and has been associated with STB in adolescent and adult populations, but data in children is lacking. We wished to study associations of asthma with childhood STB given asthma’s potential as a clinically relevant model for childhood chronic immune dysregulation.MethodsUsing data from the Adolescent Brain Cognitive Development (ABCD) Study (N=11,878, 52% males, mean age 9.9 years at baseline assessment and 10.9 years at 1-year follow up), we assessed associations between asthma and STB at both baseline and 1-year follow up.ResultsWe found that asthma at baseline assessment (n=2,214, 18.6%) is associated with STB, controlling for multiple confounders including demographics, socioeconomic factors and environmental confounders such as air pollution (odds ratio (OR)=1.2, 95%CI 1.01-1.42, P=0.039). Indicators of recently active asthma were not significantly associated with suicidality at baseline assessment (currently taking asthma medication: OR=1.22, 95%CI 0.93-1.60, P=0.146), or at 1-year follow up (past year asthma-related clinical visit: OR=1.13, 95%CI 0.87-1.47, P=0.357). Proxy-measures of asthma severity (number of asthma medications or clinical visits) did not reveal a significant dose response relationship with STB.ConclusionsFindings suggest an association between history of asthma and STB in children, which may not be related to asthma disease state. Further research is needed to investigate mechanisms underlying this relationship.

The Coronavirus Disease 2019 (COVID-19) pandemic brought unprecedented socially isolating measures to mitigate the spread of disease, heightening the importance of public outdoor urban greenspace. Here, we investigated the association between tree-rich greenspace and mental health in a large opportunity sample surveyed using a crowdsourcing research website (www.covid19resilience.org) between April 6th and October 12th, 2020 during the pandemic in the United States. Participants living in the U.S. (N = 2,089, 83.1% females, mean age 42 years, age range 18–90 years) were mapped to 1,080 unique ZIP Codes and mean tree canopy density was calculated with a 250 m buffer around each ZIP Code grouped by quartile as a proxy for nearby greenspace. Four mental health parameters were assessed: (1) COVID-19-related worries; (2) anxiety symptoms; (3) depression symptoms; and (4) a standardized and weighted composite mental health score of all three parameters. Multivariate regression analyses with multilevel models were used to study the association between nearby greenspace and the four mental health outcomes, controlling for participant demographics and ZIP Code urbanicity. In the entire cohort, increased nearby greenspace showed a significant protective effect for depression (Coef. = −0.27; p = 0.0499), and composite mental health scores (Coef. = −0.19; p = 0.038) when comparing ZIP Codes with the most greenspace to ZIP Codes with the least, with no observed effects on COVID-19 related worries or anxiety individually. Stratifying by age suggested protective trends of greenspace on mental health in older subsets of the population (top age quartile, over 51 years old) experiencing less depression (Coef. = −0.45; p = 0.048) and lower composite mental health scores (Coef. = −0.34; – = 0.032) as a function of nearby greenspace. Additionally, younger subsets of the population (second youngest age quartile, 31–38 years) experienced lower COVID-19 related worries (Coef. = −1.34; p = 0.022) as a function of greenspace. These findings may indicate that tree-rich greenspace plays a protective role on mental health during the COVID-19 pandemic, specifically in certain age groups, supporting the use of greenspace-related strategies to help mitigate mental health burden during this challenging and isolating time.

Key Points Question Are there associations among attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy, externalizing symptoms, and childhood suicidality (ie, ideation or attempts)? Findings In this cohort study of 11 878 children aged 9 to 10 years at baseline, externalizing symptoms showed expected associations with suicidality. ADHD pharmacotherapy was associated with less suicidality in children with externalizing symptoms, specifically among those with substantial symptoms burden, both at the baseline and 1-year follow-up assessment. Meaning These findings suggest that in children with substantial externalizing symptoms, ADHD medication use may be associated with less suicidality, in addition to its known clinical benefits in treating externalizing symptoms., This cohort study investigates the associations of attention-deficit/hyperactivity disorder (ADHD) medication with externalizing symptoms and childhood suicidality., Importance Childhood suicidality (ie, suicidal ideation or attempts) rates are increasing, and attention-deficit/hyperactivity disorder (ADHD) and externalizing symptoms are common risk factors associated with suicidality. More data are needed to describe associations of ADHD pharmacotherapy with childhood suicidality. Objective To investigate the associations of ADHD pharmacotherapy with externalizing symptoms and childhood suicidality. Design, Setting, and Participants In this cohort study, cross-sectional and 1-year-longitudinal associations were examined using data (collected during 2016-2019) from the Adolescent Brain Cognitive Development (ABCD) Study, a large, diverse US sample of children aged 9 to 11 years. Data analysis was performed from November to December 2020. Exposures Main and interaction associations of externalizing symptoms (hyperactivity ADHD symptoms, oppositional defiant, and conduct disorder symptoms) and ADHD medication treatment (methylphenidate and amphetamine derivatives, α-2-agonists, and atomoxetine) at baseline assessment. Main Outcomes and Measures Child-reported suicidality (past and present at baseline; current at longitudinal assessment). Covariates were age, sex, race/ethnicity, parents’ education, marital status, and concomitant child psychiatric pharmacotherapy (antidepressants and antipsychotics). Results Among 11 878 children at baseline assessment (mean [SD] age, 9.9 [0.6] years; 6196 boys [52.2%]; 8805 White [74.1%]), 1006 (8.5%) were treated with ADHD medication and 1040 (8.8%) reported past or current suicidality. Externalizing symptoms (median [range], 1 [0-29] symptom count) were associated with suicidality (for a change of 1 SD in symptoms, odds ratio [OR], 1.34; 95% CI, 1.26-1.42; P

Background Obsessive compulsive symptomatology (OCS) is common in adolescence but usually does not meet the diagnostic threshold for obsessive compulsive disorder. Nevertheless, both OCD and subthreshold OCS are associated with increased likelihood of experiencing other serious psychiatric conditions including depression and suicidal ideation. Unfortunately, there is limited information on the neurobiology of OCS. Methods Here we undertook one of the first brain imaging studies of OCS in a large adolescent sample (analyzed n=832) from the Philadelphia Neurodevelopmental Cohort. We investigated resting-state fMRI functional connectivity using complementary analytic approaches that focus on different neuroanatomical scales, from known functional systems to connectome-wide tests. Results We found a robust pattern of connectome-wide, OCS-related differences, as well as evidence of specific abnormalities involving known functional systems, including dorsal and ventral attention, frontoparietal and default mode systems. Analysis of cerebral perfusion imaging and high resolution structural imaging did not show OCS-related differences, consistent with domain specificity to functional connectivity. Conclusions The brain connectomic associations with OCS reported here, together with early studies of its clinical relevance, support the potential for OCS as an early marker of psychiatric risk that may enhance our understanding of mechanisms underlying the onset of adolescent psychopathology.

Major depressive disorder (MDD) is complex and multifactorial, posing a major challenge of tailoring the optimal medication for each patient. Current practice for MDD treatment mainly relies on trial and error, with an estimated 42–53% response rates for antidepressant use. Here, we sought to generate an accurate predictor of response to a panel of antidepressants and optimize treatment selection using a data-driven approach analyzing combinations of genetic, clinical, and demographic factors. We analyzed the response patterns of patients to three antidepressant medications in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and employed state-of-the-art machine learning (ML) tools to generate a predictive algorithm. To validate our results, we assessed the algorithm’s capacity to predict individualized antidepressant responses on a separate set of 530 patients in STAR*D, consisting of 271 patients in a validation set and 259 patients in the final test set. This assessment yielded an average balanced accuracy rate of 72.3% (SD 8.1) and 70.1% (SD 6.8) across the different medications in the validation and test set, respectively (p p’s

The COVID-19 pandemic has disproportionately impacted the well-being of vulnerable populations in the US, including Black people. The impact on pregnant women is of special concern for the intrauterine and post-natal development of their offspring. We evaluated in an online survey a sample of 913 pregnant women, 216 Black, 571 White, 126 Other, during a 2-week stay-at-home mandate in the Philadelphia region. We applied logistic regression models and analysis of covariance to examine general and pregnancy-specific worries and negative consequences arising from the COVID-19 pandemic, symptoms of anxiety and depression, and resilience. Black pregnant women reported greater likelihood of having their employment negatively impacted, more concerns about a lasting economic burden, and more worries about their prenatal care, birth experience, and post-natal needs. In the full sample, 11.1% of women met screening criteria for anxiety and 9.9% met criteria for depression. Black women were more likely to meet criteria for depression than White women, but this difference was not significant accounting for covariates. Resilience factors including self-reliance and emotion regulation were higher in Black women. Racial disparities related to COVID-19 in pregnant women can advance the understanding of pregnancy related stressors and improve early identification of mental health needs.

COVID-19 pandemic is a global calamity posing an unprecedented opportunity to study resilience. We developed a brief resilience survey probing self-reliance, emotion-regulation, interpersonal-relationship patterns and neighborhood-environment, and applied it online during the acute COVID-19 outbreak (April 6–15, 2020), on a crowdsourcing research website (www.covid19resilience.org) advertised through social media. We evaluated level of stress (worries) regarding COVID-19: (1) contracting, (2) dying from, (3) currently having, (4) family member contracting, (5) unknowingly infecting others with (6) experiencing significant financial burden following. Anxiety (GAD7) and depression (PHQ2) were measured. Totally, 3042 participants (n = 1964 females, age range 18–79, mean age = 39) completed the resilience and COVID-19-related stress survey and 1350 of them (mean age = 41, SD = 13; n = 997 females) completed GAD7 and PHQ2. Participants significantly endorsed more distress about family contracting COVID-19 (48.5%) and unknowingly infecting others (36%), than getting COVID-19 themselves (19.9%), p 10, 22.2%) and depression (PHQ2 > 2, 16.1%) did not differ between healthcare providers and non-healthcare providers. Higher resilience scores were associated with lower COVID-19 related worries (main effect F1,3054 = 134.9; p

Accumulating data suggest an association between inflammation and schizophrenia and related psychosis. While several studies have established this immune-psychosis association in adult schizophrenia patients, there is very limited data associating inflammation with acute psychosis in children and adolescents. The ratio between neutrophils and lymphocyte, computed from routine blood counts, has been shown to correlate with traditional markers of inflammation, and is therefore considered a proxy-marker for inflammation. Here we report elevated neutrophil to lymphocyte ratio and total leukocyte count in psychotic adolescent inpatients (n = 81, mean age 14.7 years, 52% males) compared to non-psychotic adolescent inpatient (n = 285, mean age 15.9 years, 58% males), in a population of adolescent inpatients with no affective symptomatology. The elevated neutrophil to lymphocyte ratio remained significant after controlling for confounders such as age, BMI, smoking and antipsychotic medication. In a subset of psychotic adolescent inpatients (n = 20, mean duration between blood test 157 days), we found significant decrease in neutrophil to lymphocyte ratio at clinical remission compared with the acute psychotic state. The results suggest that psychosis is associated with peripheral markers of inflammation early in the course of psychiatric pathology, and that inflammation may represent a state that accompanies psychosis and decreases during clinical remission.

The interplay between the immune system and behaviour is of increasing interest in psychiatry research. Specifically, accumulating data points to a link between inflammation and psychopathology, including affective symptomatology. We investigated the association between inflammation and affective polarity in psychiatric inpatients who were hospitalized due to an affective exacerbation. Data was collected retrospectively and comparisons were made between manic and depressed patients. C-reactive protein (CRP), a general laboratory marker of immune activation and inflammation, was used as a non-specific inflammatory biomarker. Age, smoking and body mass index were considered covariates. Manic polarity (n = 89) was associated with statistically significant elevated CRP levels compared to depressed polarity (n = 44, 56%; p = 0.036), after controlling for covariates. No differences were observed in CRP levels across Diagnostic and Statistical Manual of Mental Disorders-IV Edition-Text Revised psychiatric diagnoses. These findings suggest a transdiagnostic association between inflammation and manic polarity in affective inpatients.

Importance Low socioeconomic status (L-SES) and the experience of traumatic stressful events (TSEs) are environmental factors implicated in behavioral deficits, abnormalities in brain development, and accelerated maturation. However, the relative contribution of these environmental factors is understudied. Objective To compare the association of L-SES and TSEs with psychopathology, puberty, neurocognition, and multimodal neuroimaging parameters in brain maturation. Design, Setting, and Participants The Philadelphia Neurodevelopmental Cohort is a community-based study examining psychopathology, neurocognition, and neuroimaging among participants recruited through the Children’s Hospital of Philadelphia pediatric network. Participants are youths aged 8 to 21 years at enrollment with stable health and fluency in English. The sample of 9498 participants was racially (5298 European ancestry [55.8%], 3124 African ancestry [32.9%], and 1076 other [11.4%]) and economically diverse. A randomly selected subsample (n = 1601) underwent multimodal neuroimaging. Data were collected from November 5, 2009, through December 30, 2011, and analyzed from February 1 through November 7, 2018. Main Outcomes and Measures The following domains were examined: (1) clinical, including psychopathology, assessed with a structured interview based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children, and puberty, assessed with the Tanner scale; (2) neurocognition, assessed by the Penn Computerized Neurocognitive Battery; and (3) multimodal magnetic resonance imaging parameters of brain structure and function. Results A total of 9498 participants were included in the analysis (4906 [51.7%] female; mean [SD] age, 14.2 [3.7] years). Clinically, L-SES and TSEs were associated with greater severity of psychiatric symptoms across the psychopathology domains of anxiety/depression, fear, externalizing behavior, and the psychosis spectrum. Low SES showed small effect sizes (highest for externalizing behavior, 0.306 SD; 95% CI, 0.269 to 0.342), whereas TSEs had large effect sizes, with the highest in females for anxiety/depression (1.228 SD; 95% CI, 1.156 to 1.300) and in males for the psychosis spectrum (1.099 SD; 95% CI, 1.032 to 1.166). Both were associated with early puberty. Cognitively, L-SES had moderate effect sizes on poorer performance, the greatest being on complex cognition (−0.500 SD 95% CI, −0.536 to −0.464), whereas TSEs were associated with slightly better memory (0.129 SD; 95% CI, 0.084 to 0.174) and poorer complex reasoning (−0.109 SD; 95% CI, −0.154 to −0.064). Environmental factors had common and distinct associations with brain structure and function. Structurally, both were associated with lower volume, but L-SES had correspondingly lower gray matter density, whereas TSEs were associated with higher gray matter density. Functionally, both were associated with lower regional cerebral blood flow and coherence and with accelerated brain maturation. Conclusions and Relevance Low SES and TSEs are associated with common and unique differences in symptoms, neurocognition, and structural and functional brain parameters. Both environmental factors are associated with earlier completion of puberty by physical features and brain parameters. These findings appear to underscore the need for identifying and preventing adverse environmental conditions associated with neurodevelopment.

Classifying patients’ affect is a pivotal part of the mental status examination. However, this common practice is often widely inconsistent between raters. Recent advances in the field of Facial Action Recognition (FAR) have enabled the development of tools that can act to identify facial expressions from videos. In this study, we aimed to explore the potential of using machine learning techniques on FAR features extracted from videotaped semi-structured psychiatric interviews of 25 male schizophrenia inpatients (mean age 41.2 years, STD = 11.4). Five senior psychiatrists rated patients’ affect based on the videos. Then, a novel computer vision algorithm and a machine learning method were used to predict affect classification based on each psychiatrist affect rating. The algorithm is shown to have a significant predictive power for each of the human raters. We also found that the eyes facial area contributed the most to the psychiatrists’ evaluation of the patients’ affect. This study serves as a proof-of-concept for the potential of using the machine learning FAR system as a clinician-supporting tool, in an attempt to improve the consistency and reliability of mental status examination.

Exposure to gestational stress is implicated in increased risk for neuropsychiatric disorders in offspring. We assessed association between prenatal exposure to a one month period of repeated rocket attacks during the 2006 Second Lebanon War in Northern Israel and emergence of childhood neuropsychiatric disorders from birth through nine years of age. Children born to women who were pregnant during the war (N=6,999) were identified and compared to children in the same district born a year later (N=7,054), whose mothers were not exposed to rocket attacks during pregnancy. Multivariable regression models assessed risk for attention deficit hyperactivity disorder, autism, epilepsy, depression and/or anxiety, or any of these disorders (composite outcome) in offspring. Models controlled for multiple confounders including parents’ demographics, parity, maternal use of psychotropic medications during pregnancy, post-partum depression and parental psychiatric history. Results show that exposed and comparison groups did not differ with respect to demographics, parity or psychiatric history. Exposed and comparison groups were similar with regards to gestational age and weight at birth. Multivariable models did not demonstrate an association between exposure to rocket attacks during pregnancy and neuropsychiatric outcomes by age nine. No interactions were found between exposure and gestational trimester at exposure or child’s sex. Our findings suggest that in utero exposure to isolated, one month repeated rocket attacks on a civilian population was not associated with major neuropsychiatric outcomes in children by age nine. Future studies should evaluate whether this exposure is associated with psychiatric and/or other health-related outcomes later in life.

BACKGROUND Psychotic and affective exacerbations associated with synthetic cannabinoid (SC) use are becoming an emerging concern in psychiatric hospitals. However, data are lacking regarding whether clinical manifestations of SC use differ from those associated with cannabis use. OBJECTIVE Our aim was to explore the unique profile of SC users admitted to a mental health center in terms of demographic, clinical, and physiologic variables in comparison to cannabis users. METHODS We retrieved retrospective data of patients admitted to a mental health center between October 2007 and May 2014 who self-reported recent use of SC (n = 60) and patients who were cannabis users (positive carboxy-tetrahydrocannabinol urine test at admission) without a history of SC use (n = 163). Clinical measures included hospitalization length, number of previous hospitalizations, Positive and Negative Syndrome Scale (PANSS) scores, psychiatric status at admission, and relevant physiologic and laboratory parameters. RESULTS Hospitalized SC users were younger than hospitalized cannabis users (n = 163) (30.46 ± 7.83 years versus 34.67 ± 10.07 years, U₂₂₃ = 3,781.5, P = .009, respectively). SC patients had longer hospitalizations compared to cannabis users (43.45 ± 54.02 days versus 22.91 ± 31.36 days, U₂₁₉ = 5,701.5, P = .005, respectively), had more previous hospitalizations (3.73 ± 5.05 versus 1.98 ± 5.12, U₂₂₃ = 6,284, P < .001, respectively), and were more likely to be hospitalized by criminal court order (36.7% [n = 22] versus 19.9% [n = 32], χ²₂ = 7.136, P = .028, respectively). SC patients presented with a more severe clinical picture manifested by higher total PANSS scores (82.53 ± 23.05 versus 69.98 ± 19.94, t₉₁ = -2.696, P = .008) in a subset of patients with PANSS scores assessed within a week from admission (n = 30 in the SC group and n = 63 in the cannabis group). No differences were found in physiologic or laboratory measures on admission between the SC and cannabis groups. CONCLUSIONS Patients admitted following use of SC are generally younger males who have higher severity of psychotic symptoms at admission, are more likely to be admitted by criminal court order, and require longer hospitalization periods in comparison to cannabis users.

Background Obsessive-compulsive symptoms (OCS) in youth are common, have heterogeneous manifestations, and have been shown to be associated with serious psychopathology. While early-life trauma exposure is associated with increased risk for obsessive-compulsive disorder (OCD), its association with different OCS and its clinical relevance for serious psychopathology is unclear. Here we aimed to evaluate associations among traumatic stressful events (TSE), OCS, and serious psychiatric conditions in community youth. Methods We studied nonmental-help seeking youths from the Philadelphia Neurodevelopmental Cohort (N = 7054, aged 11-21, 54% females, 52% prepubertal), assessed for lifetime TSE exposure and OCS. Regression models investigated cross-sectional associations of TSEs with OCS, and associations with depression, suicide ideation and psychosis. Models examined sex and puberty effects, controlling for age and socioeconomic status. Results Trauma exposure was associated with higher OCS rates, especially in females (Trauma × Sex interaction Wald = 7.93, p = 0.005) and prepuberty (Trauma × Puberty interaction Wald = 7.68, p = 0.006). TSEs were associated with all OCS manifestations, most prominently with bad intrusive thoughts (odds ratio [OR] = 1.63). Assaultive TSEs, especially sexual assault, showed stronger associations with OCS compared with nonassaultive TSEs. While TSEs and OCS were independently associated with depression, suicide ideation, and psychosis, a significant interaction was observed only in association with increased rates of psychosis (Trauma × OCS interaction Wald = 5.08, p = 0.024). Conclusion Early-life trauma is associated with OCS in a dose-response manner, more so in females and prepuberty. The trauma-OCS association varied by load, type of trauma, and by OCS subtypes. Trauma-OCS appears a detrimental combination in association with psychosis.

OBJECTIVES: To examine agreement between parent and adolescent reports of adolescents’ suicidal thoughts and explore demographic and clinical factors associated with agreement in a large community sample. METHODS: Participants included 5137 adolescents 11 to 17 years old (52.1% girls; 43.0% racial minority) and a collateral informant (97.2% parent or stepparent) from the Philadelphia Neurodevelopmental Cohort. Families were recruited from a large pediatric health care network. Adolescents and parents completed a clinical interview that included questions about adolescents’ lifetime suicidal thoughts. RESULTS: Agreement was moderate for thoughts of killing self (κ = 0.466) and low for thoughts of death or dying (κ = 0.171). Discrepancies stemmed from both parental unawareness of suicidal thoughts reported by adolescents and adolescent denial of suicidal thoughts reported by parents. Fifty percent of parents were unaware of adolescents’ thoughts of killing themselves, and 75.6% of parents were unaware of adolescents’ recurrent thoughts of death. Forty-eight percent of adolescents denied thoughts of killing themselves, and 67.5% of adolescents denied thoughts of death reported by parents. Several demographic (eg, age) and clinical (eg, treatment history) characteristics were associated with agreement. CONCLUSIONS: Early identification and intervention hinge on reliable and valid assessment of suicide risk. The high prevalence of parental unawareness and adolescent denial of suicidal thoughts found in this study suggests that many adolescents at risk for suicide may go undetected. These findings have important clinical implications for pediatric settings, including the need for a multi-informant approach to suicide screening and a personalized approach to assessment based on empirically derived risk factors for unawareness and denial.

Summary Background Many countries are developing suicide prevention strategies for which up-to-date, high-quality evidence is required. We present updated evidence for the effectiveness of suicide prevention interventions since 2005. Methods We searched PubMed and the Cochrane Library using multiple terms related to suicide prevention for studies published between Jan 1, 2005, and Dec 31, 2014. We assessed seven interventions: public and physician education, media strategies, screening, restricting access to suicide means, treatments, and internet or hotline support. Data were extracted on primary outcomes of interest, namely suicidal behaviour (suicide, attempt, or ideation), and intermediate or secondary outcomes (treatment-seeking, identification of at-risk individuals, antidepressant prescription or use rates, or referrals). 18 suicide prevention experts from 13 European countries reviewed all articles and rated the strength of evidence using the Oxford criteria. Because the heterogeneity of populations and methodology did not permit formal meta-analysis, we present a narrative analysis. Findings We identified 1797 studies, including 23 systematic reviews, 12 meta-analyses, 40 randomised controlled trials (RCTs), 67 cohort trials, and 22 ecological or population-based investigations. Evidence for restricting access to lethal means in prevention of suicide has strengthened since 2005, especially with regard to control of analgesics (overall decrease of 43% since 2005) and hot-spots for suicide by jumping (reduction of 86% since 2005, 79% to 91%). School-based awareness programmes have been shown to reduce suicide attempts (odds ratio [OR] 0·45, 95% CI 0·24–0·85; p=0·014) and suicidal ideation (0·5, 0·27–0·92; p=0·025). The anti-suicidal effects of clozapine and lithium have been substantiated, but might be less specific than previously thought. Effective pharmacological and psychological treatments of depression are important in prevention. Insufficient evidence exists to assess the possible benefits for suicide prevention of screening in primary care, in general public education and media guidelines. Other approaches that need further investigation include gatekeeper training, education of physicians, and internet and helpline support. The paucity of RCTs is a major limitation in the evaluation of preventive interventions. Interpretation In the quest for effective suicide prevention initiatives, no single strategy clearly stands above the others. Combinations of evidence-based strategies at the individual level and the population level should be assessed with robust research designs. Funding The Expert Platform on Mental Health, Focus on Depression, and the European College of Neuropsychopharmacology.

Objective Obsessive-compulsive symptoms (OCS) are common throughout development and often considered developmentally appropriate. We evaluated the prevalence and phenotypic heterogeneity of self-reported OCS in a large community youth sample not ascertained for seeking mental-health help. We aimed to identify patterns in OCS that are associated with serious psychopathology and may thus represent a “red flag” that merits psychiatric evaluation. Method Data were analyzed from youth from the Philadelphia Neurodevelopmental Cohort (N = 7,054, aged 11−21 years, 54% female). Participants underwent structured psychiatric interviews, including screening for OCS (8 obsessions, 8 compulsions, and hoarding) and other major psychopathology domains. Factor analysis was conducted to identify clustering of OCS presentation. Regression models were used to investigate association of OCS with threshold lifetime diagnoses of obsessive-compulsive disorder (OCD), depressive episode, psychosis, and suicide ideation. Results OCS were common in non−mental health−seeking individuals (38.2%), although only 3% met threshold OCD criteria. OCS were more common in female participants and postpuberty. Factor analyses resulted in 4 factors: F1 – Bad Thoughts; F2 − Repeating/Checking; F3 – Symmetry; F4 – Cleaning/Contamination; and Hoarding as a separate item. All OCS were associated with higher rates of OCD, depression, psychosis, and suicide ideation. However, endorsement of F1 symptoms, prevalent in more than 20% of the sample, showed the most substantial associations with major psychiatric conditions. Conclusion OCS are common in community youth. Although for most youths OCS symptoms may be benign, some patterns of OCS are associated with major psychiatric conditions. These findings may help to identify youth at risk for serious psychopathology.

Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine strategies in brain diseases. Experimental studies have shown that repeated administration of phencyclidine (PCP) leads to schizophrenia-like behavioral changes in mice. The aim of the present study was to explore the effectiveness of MSC transplantation into the hippocampus in attenuating PCP-induced social behavior deficits. PCP was administered subcutaneously to C57bl mice (10 mg/kg daily) for 2 weeks. On the first day of PCP administration, adult human MSCs were transplanted into the hippocampus. A week after the last PCP dose, the mice underwent social preference testing. MSC transplantation was associated with a significant reduction in the adverse social behavior induced by PCP. Immunohistochemical analysis revealed that the stem cells survived in the mouse brain, and hippocampal Western blot analysis revealed a statistical trend towards a decrease in cleaved caspase 3 protein levels in the stem cell treated group. Upon in vitro co-culture of astrocytes and MSCs, the MSCs, in the presence of PCP, positively regulated astrocyte expression of genes involved in glutamate metabolism and antioxidant defenses. These findings suggest that MSC transplantation into the hippocampus may serve as a novel neuroprotective tool for the treatment of the PCP-induced schizophrenia-like social endophenotype. The mechanism underlying the beneficial behavioral effect may involve modulation of host astrocyte functioning, including glutamate processing and antioxidant capacity.

Huntington's disease (HD) is a hereditary, progressive and ultimately fatal neurodegenerative disorder. Excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. Recently we developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF+ cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. Here, the efficacy of NTF+ cells was evaluated using the quinolinic acid (QA) rat model for excitotoxicity. We show that NTF+ cells transplanted into rat brains after QA injection survive transplantation (19% after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF+ cells exhibit improved behavior; namely, perform 80% fewer apomorphine induced rotations than PBS-treated QA-injected rats. Importantly, we found that MSCs derived from HD patients can be induced to become NTF+ cells and exert efficacious effects similarly to NTF+ cells derived from healthy donors. To our knowledge, this is the first study to take adult bone marrow derived mesenchymal stem cells from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI we demonstrate in vivo that PBS-treated QA-injected striatae exhibit increasing T2 values over time in lesioned regions, whereas T2 values decrease in equivalent regions of QA-injected rats treated with NTF+ cells. We conclude that NTF cellular treatment could serve as a novel therapy for managing HD.

The glycosaminoglycan hyaluronic acid (HA) is an important component of the extracellular matrix (ECM) in the brain. CD44 is a cell adhesion molecule that binds to HA in the ECM and is present on astrocytes, microglia and certain neurons. Cell adhesion molecules have been reported to be involved in anxiety and mood disorders. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in brain GWAS studies as a possible risk gene for suicidal behavior.We measured the CSF levels of HA and the soluble CD44 (sCD44) in suicide attempters (n=94) and in healthy controls (n=45) using ELISA and electrochemiluminescence assays. We also investigated other proteins known to interact with CD44, such as osteopontin and the matrix metalloproteinases MMP1, MMP3 and MMP9.The suicide attempters had higher CSF levels of HA (p=.003) and MMP9 (p=.004). The CSF levels of HA correlated with BBB-permeability (rho=0.410, p.001) and MMP9 correlated with sCD44 levels (rho=0.260, p=.005).Other relevant biological contributors to suicidal behavior is not addressed in parallel to the specific role of CD44-HA signaling. The gender distribution of the patients from whom CSF was analyzed was uneven.Increased BBB-permeability and HA levels might be a results of increased neuroinflammation and can play a role in the pathobiology of suicidal behavior. The CD44 signaling pathway might be considered a novel target for intervention in mood disorders.

Stem cell-based therapy holds great potential for future treatment of multiple sclerosis (MS). Bone marrow mesenchymal stem cells (MSCs) were previously reported to ameliorate symptoms in mouse MS models (experimental autoimmune encephalomyelitis, EAE). In this study, we induced MSCs to differentiate in vitro into neurotrophic factor-producing cells (NTFCs). Our main goal was to examine the clinical use of NTFCs on EAE symptoms. The NTFCs and MSCs were transplanted intracerebroventricularly (ICV) to EAE mice. We found that NTFCs transplantations resulted in a delay of symptom onset and increased animal survival. Transplantation of MSCs also exerted a positive effect but to a lesser extent. In vitro analysis demonstrated the NTFCs' capacity to suppress mice immune cells and protect neuronal cells from oxidative insult. Our results indicate that NTFCs-transplanted ICV delay disease symptoms of EAE mice, possibly via neuroprotection and immunomodulation, and may serve as a possible treatment to MS.