Developmental pathway for first onset of depressive disorders in females: from adolescence to emerging adulthood.

BACKGROUND: Although risk markers for depressive disorders (DD) are dynamic, especially during adolescence, few studies have examined how change in risk levels during adolescence predict DD onset during transition to adulthood. We compared two competing hypotheses of the dynamic effects of risk. The risk escalation hypothesis posits that worsening of risk predicts DD onset beyond risk level. The chronic risk hypothesis posits that persistently elevated risk level, rather than risk change, predicts DD onset. METHODS: Our sample included 393 girls (baseline age 13.5-15.5 years) from the adolescent development of emotions and personality traits project. Participants underwent five diagnostic interviews and assessments of risk markers for DD at 9-month intervals and were re-interviewed at a 6-year follow-up. We focused on 17 well-established risk markers. For each risk marker, we examined the prospective effects of risk level and change on first DD onset at wave six, estimated by growth curve modeling using data from the first five waves. RESULTS: For 13 of the 17 depression risk markers, elevated levels of risk during adolescence, but not change in risk, predicted first DD onset during transition to adulthood, supporting the chronic risk hypothesis. Minimal evidence was found for the risk escalation hypothesis. CONCLUSIONS: Participants who had a first DD onset during transition to adulthood have exhibited elevated levels of risk throughout adolescence. Researchers and practitioners should administer multiple assessments and focus on persistently elevated levels of risk to identify individuals who are most likely to develop DD and to provide targeted DD prevention.

Associations between polygenic risk scores for cardiometabolic phenotypes and adolescent depression and body dissatisfaction.

BACKGROUND: Adolescents with elevated body mass index (BMI) are at an increased risk for depression and body dissatisfaction. Type 2 diabetes (T2D) is an established risk factor for depression. However, shared genetic risk between cardiometabolic conditions and mental health outcomes remains understudied in youth. METHODS: The current study examined associations between polygenic risk scores (PRS) for BMI and T2D, and symptoms of depression and body dissatisfaction, in a sample of 827 community adolescents (Mage = 13.63, SDage = 1.01; 76% girls). BMI, depressive symptoms, and body dissatisfaction were assessed using validated self-report questionnaires. RESULTS: BMI-PRS was associated with phenotypic BMI (ß = 0.24, p < 0.001) and body dissatisfaction (ß = 0.17, p < 0.001), but not with depressive symptoms. The association between BMI-PRS and body dissatisfaction was significantly mediated by BMI (indirect effect = 0.10, CI [0.07-0.13]). T2D-PRS was not associated with depression or body dissatisfaction. CONCLUSIONS: The results suggest phenotypic BMI may largely explain the association between genetic risk for elevated BMI and body dissatisfaction in adolescents. Further research on age-specific genetic effects is needed, as summary statistics from adult discovery samples may have limited utility in youth. IMPACT: The association between genetic risk for elevated BMI and body dissatisfaction in adolescents may be largely explained by phenotypic BMI, indicating a potential pathway through which genetic predisposition influences body image perception. Furthermore, age-specific genetic research is needed to understand the unique influences on health outcomes during adolescence. By identifying BMI as a potential mediator in the association between genetic risk for elevated BMI and body dissatisfaction, the current findings offer insights that could inform interventions targeting body image concerns and mental health in this population.

Dynamic risk for first onset of depressive disorders in adolescence: does change matter?

BACKGROUND: Risk factors for depressive disorders (DD) change substantially over time, but the prognostic value of these changes remains unclear. Two basic types of dynamic effects are possible. The 'Risk Escalation hypothesis' posits that worsening of risk levels predicts DD onset above average level of risk factors. Alternatively, the 'Chronic Risk hypothesis' posits that the average level rather than change predicts first-onset DD. METHODS: We utilized data from the ADEPT project, a cohort of 496 girls (baseline age 13.5-15.5 years) from the community followed for 3 years. Participants underwent five waves of assessments for risk factors and diagnostic interviews for DD. For illustration purposes, we selected 16 well-established dynamic risk factors for adolescent depression, such as depressive and anxiety symptoms, personality traits, clinical traits, and social risk factors. We conducted Cox regression analyses with time-varying covariates to predict first DD onset. RESULTS: Consistently elevated risk factors (i.e. the mean of multiple waves), but not recent escalation, predicted first-onset DD, consistent with the Chronic Risk hypothesis. This hypothesis was supported across all 16 risk factors. CONCLUSIONS: Across a range of risk factors, girls who had first-onset DD generally did not experience a sharp increase in risk level shortly before the onset of disorder; rather, for years before onset, they exhibited elevated levels of risk. Our findings suggest that chronicity of risk should be a particular focus in screening high-risk populations to prevent the onset of DDs. In particular, regular monitoring of risk factors in school settings is highly informative.

Pathways from performance monitoring to negative symptoms and functional outcomes in psychotic disorders.

BACKGROUND: Performance monitoring entails rapid error detection to maintain task performance. Impaired performance monitoring is a candidate pathophysiological process in psychotic disorders, which may explain the broader deficit in executive function and its known associations with negative symptoms and poor functioning. The current study models cross-sectional pathways bridging neurophysiological measures of performance monitoring with executive function, symptoms, and functioning. METHODS: Data were from the 20-year assessment of the Suffolk County Mental Health Project. Individuals with psychotic disorders (N = 181) were originally recruited from inpatient psychiatric facilities. Data were also collected from a geographically and demographically matched group with no psychosis history (N = 242). Neural measures were the error-related negativity (ERN) and error positivity (Pe). Structural equation modeling tested mediation pathways. RESULTS: Blunted ERN and Pe in the clinical cohort related to impaired executive function (r = 0.26-0.35), negative symptom severity (r = 0.17-0.25), and poor real-world functioning (r = 0.17-0.19). Associations with executive function were consistent across groups. Multiple potential pathways were identified in the clinical cohort: reduced ERN to inexpressivity was mediated by executive function (ß = 0.10); reduced Pe to global functioning was mediated by executive function and avolition (ß = 0.10). CONCLUSIONS: This supports a transdiagnostic model of psychotic disorders by which poor performance monitoring contributes to impaired executive function, which contributes to negative symptoms and poor real-world functioning. If supported by future longitudinal research, these pathways could inform the development of targeted interventions to address cognitive and functional deficits that are central to psychotic disorders.

Differential outcomes of tonic and phasic irritability in adolescent girls.

BACKGROUND: Irritable mood is a transdiagnostic clinical feature that is present in multiple psychiatric disorders. Although irritability is frequently examined as a unitary construct, two dimensions of irritability, tonic (i.e., irritable mood) and phasic (i.e., temper outbursts), have been hypothesized. However, few studies have examined whether tonic and phasic irritability are empirically separable and predict different forms of psychopathology. METHODS: We utilized data from a longitudinal study of a community sample of 550 girls (age 13.5-15.5 years) followed at 9-month intervals for 3 years. We conducted exploratory factor analysis (EFA) using items from three self-report inventories: the International Personality Item Pool Anger scale, Temperament and Affectivity Inventory Anger scale, and Buss-Perry Aggression Questionnaire Anger scale. RESULTS: The EFA identified dimensions that were consistent with tonic and phasic irritability. Tonic irritability at baseline independently predicted the development of depressive disorders and generalized anxiety disorder (GAD) in subsequent waves. Phasic irritability independently predicted a decreased probability of GAD, but an increased probability of oppositional defiant, conduct, and substance use disorder, and greater risky sexual behavior and relational aggression during the follow-up. CONCLUSIONS: Tonic and phasic irritability appear to be separable constructs with unique implications for later psychopathology and related behavior among adolescent girls. It is important to consider this distinction in research on the etiology and pathophysiology of irritability and developing effective treatments.

Prediction of lithium treatment response in bipolar depression using 5-HTT and 5-HT1A PET.

BACKGROUND: Lithium, one of the few effective treatments for bipolar depression (BPD), has been hypothesized to work by enhancing serotonergic transmission. Despite preclinical evidence, it is unknown whether lithium acts via the serotonergic system. Here we examined the potential of serotonin transporter (5-HTT) or serotonin 1A receptor (5-HT1A) pre-treatment binding to predict lithium treatment response and remission. We hypothesized that lower pre-treatment 5-HTT and higher pre-treatment 5-HT1A binding would predict better clinical response. Additional analyses investigated group differences between BPD and healthy controls and the relationship between change in binding pre- to post-treatment and clinical response. Twenty-seven medication-free patients with BPD currently in a depressive episode received positron emission tomography (PET) scans using 5-HTT tracer [11C]DASB, a subset also received a PET scan using 5-HT1A tracer [11C]-CUMI-101 before and after 8 weeks of lithium monotherapy. Metabolite-corrected arterial input functions were used to estimate binding potential, proportional to receptor availability. Fourteen patients with BPD with both [11C]DASB and [11C]-CUMI-101 pre-treatment scans and 8 weeks of post-treatment clinical scores were included in the prediction analysis examining the potential of either pre-treatment 5-HTT or 5-HT1A or the combination of both to predict post-treatment clinical scores. RESULTS: We found lower pre-treatment 5-HTT binding (p = 0.003) and lower 5-HT1A binding (p = 0.035) were both significantly associated with improved clinical response. Pre-treatment 5-HTT predicted remission with 71% accuracy (77% specificity, 60% sensitivity), while 5-HT1A binding was able to predict remission with 85% accuracy (87% sensitivity, 80% specificity). The combined prediction analysis using both 5-HTT and 5-HT1A was able to predict remission with 84.6% accuracy (87.5% specificity, 60% sensitivity). Additional analyses BPD and controls pre- or post-treatment, and the change in binding were not significant and unrelated to treatment response (p > 0.05). CONCLUSIONS: Our findings suggest that while lithium may not act directly via 5-HTT or 5-HT1A to ameliorate depressive symptoms, pre-treatment binding may be a potential biomarker for successful treatment of BPD with lithium. CLINICAL TRIAL REGISTRATION: PET and MRI Brain Imaging of Bipolar Disorder Identifier: NCT01880957; URL: https://clinicaltrials.gov/ct2/show/NCT01880957.

Testing explanatory models of the interplay between depression, neuroticism, and stressful life events: a dynamic trait-stress generation approach.

BACKGROUND: Classic conceptual frameworks explaining the relationship of personality traits to depression include the precursor and predisposition models. The former hypothesizes that depression is predicted by traits alone whereas the latter hypothesizes that stress, together with personality, predicts depression. Dynamic vulnerability models (DVM) expand on these perspectives by incorporating fluctuations in personality over time. The stress generation model provides an alternative view, positing that depression generates stress, creating a self-perpetuating cycle. However, these conceptual models are rarely directly compared. METHOD: We tested these models, focusing on neuroticism and stressful life events that the participant may have contributed to, using path analysis in a sample of 550 never-depressed, adolescent females assessed five times over 3 years. RESULTS: A dynamic precursor model with stress generation was best supported. For the precursor component, neuroticism predicted subsequent depression across four assessment intervals. For the dynamic trait component, stressful life events predicted subsequent neuroticism at three of four intervals. Finally, in line with stress generation, depression consistently predicted subsequent stressful life events, and life events then predicted depression. CONCLUSIONS: Finding support for the DVM is noteworthy, as this is the first comprehensive test of this model. Moreover, results supported integrating stress generation with trait vulnerability. Continued use of integrated approaches and refining the statistical implementation of these theories is necessary to advance understanding of the development of depression.

Intrinsic neural circuitry of depression in adolescent females.

BACKGROUND: Adolescence is characterized by affective and cognitive changes that increase vulnerability to depression, especially in females. Neurodevelopmental models attribute adolescent depression to abnormal responses in amygdala, striatum, and prefrontal cortex (PFC). We examined whether the strength of functional brain networks involving these regions predicts depression symptoms in adolescent females. METHODS: In this longitudinal study, we recorded resting-state functional connectivity (RSFC) in 174 adolescent females. Using a cross-validation strategy, we related RSFC profiles that included (a) a network consisting of amygdala, striatum, and PFC (within-circuit model), (b) connectivity of this network to the whole brain (extended-circuit model), and (c) a network consisting of the entire brain (whole-brain model) to depression symptoms assessed concurrently and 18 months later. RESULTS: In testing subsets, the within-circuit RSFC profiles were associated with depression symptoms concurrently and 18 months later, while the extended-circuit and whole-brain model did not explain any additional variance in depression symptoms. Connectivity related to anterior cingulate and ventromedial prefrontal cortex contributed most to the association. CONCLUSIONS: Our results demonstrate that RSFC-based brain networks that include amygdala, striatum, and PFC are stable neural signatures of concurrent and future depression symptoms, representing a significant step toward identifying the neural mechanism of depression in adolescence.

Meta-analysis of aberrant post-error slowing in substance use disorder: implications for behavioral adaptation and self-control.

Individual with substance use disorders have well-recognized impairments in cognitive control, including in behavioral adaptation after mistakes. One way in which this impairment manifests is via diminished post-error slowing, the increase in reaction time following a task-related error that is posited to reflect cautionary or corrective behavior. Yet, in the substance use disorder literature, findings with regard to post-error slowing have been inconsistent, and thus could benefit from quantitative integration. Here, we conducted a meta-analysis of case-control studies examining post-error slowing in addiction. Twelve studies with 15 unique comparisons were identified, comprising 567 substance users and 384 healthy controls across three broad types of inhibitory control paradigms (go-no/go, conflict resolution, and stop signal tasks, respectively). Results of the random-effects meta-analysis revealed a moderate group difference across all studies (Cohen's d = 0.31), such that the individuals with substance use disorder had diminished post-error slowing compared with controls. Despite this omnibus effect, there was also large variability in the magnitude of the effects, explained in part by differences between studies in task complexity. These findings suggest that post-error slowing may serve as a promising and easy-to-implement measure of cognitive control impairment in substance use disorder, with potential links to aberrant brain function in cognitive control areas such as the anterior cingulate cortex.

The short-term reliability and long-term stability of salivary immune markers.

Salivary markers of immune function are increasingly commonly used in studies of human health. Yet, few studies have examined the short-term or long-term reliability or stability of these biomarkers, making their measurement properties unclear. We addressed this issue in the present study by collecting two saliva samples, two hours apart, from 426 adolescent girls during a baseline laboratory visit. Then, eighteen months later, we collected the same samples again from a subset of these participants (n = 113). The correlations between the two samples collected at each session were generally high (mean r = 0.67). In contrast, although single saliva samples were only weakly correlated across 18 month (mean rs = 0.18), averaging the two quantifications within a session considerably improved the reliability (mean r = 0.27). In short, salivary immune markers exhibited strong short-term test-retest correlations, and averaging across multiple assessments notably improved long-term test-retest correlations. Additional research is needed to establish the health relevance and mechanisms underlying these potentially useful, non-invasive biomarkers.

Trait and facet-level predictors of first-onset depressive and anxiety disorders in a community sample of adolescent girls.

BACKGROUND: Individual differences in neuroticism, extraversion, and conscientiousness are associated with, and may predict onset of, internalizing disorders. These general traits can be parsed into facets, but there is a surprising paucity of research on facet risk for internalizing disorders. We examined general traits and facets of neuroticism, extraversion, and conscientiousness in predicting first onsets of depressive and anxiety disorders. METHODS: A community sample of 550 adolescent females completed general and facet-level personality measures and diagnostic interviews. Interviews were re-administered 18 months later. RESULTS: First onsets of depressive disorders were predicted by neuroticism, extraversion, and conscientiousness. Facets predicting first onset of depression included depressivity (neuroticism facet) and lower positive emotionality and sociability (extraversion facets). First onsets of generalized anxiety disorder (GAD) were predicted by neuroticism, and particularly the facet of anxiousness. First onsets of social phobia were predicted at the facet level by anxiousness. First onsets of specific phobia were predicted by neuroticism, low conscientiousness, and all neuroticism facets. In multivariate analyses, first onsets of depression were uniquely predicted by depressivity, and onsets of GAD and social phobia were uniquely predicted by anxiousness over and above the general trait of neuroticism. CONCLUSIONS: General traits predict first onsets of depressive and anxiety disorders. In addition, more specific associations are evident at the facet level. Facets can refine our understanding of the links between personality and psychopathology risk, and provide finer-grained targets for personality-informed interventions.

A neural biomarker, the error-related negativity, predicts the first onset of generalized anxiety disorder in a large sample of adolescent females.

OBJECTIVE: An increased neural response to making mistakes has emerged as a potential biomarker of anxiety across development. The error-related negativity (ERN) is an event-related potential elicited when people make mistakes on simple laboratory-based reaction time tasks that has been associated with risk for anxiety. This study examined whether the ERN prospectively predicted the first onset of generalized anxiety disorder (GAD) over 1.5 years in adolescent girls. METHODS: The sample included 457 girls between the ages of 13.5 and 15.5 years, with no history of GAD. At baseline, the ERN was measured using a flankers task. Psychiatric history of the adolescent and biological parent was assessed with diagnostic interviews, and the adolescent completed a self-report questionnaire regarding anxiety symptoms. Approximately 1.5 years later, adolescents completed the same interview. RESULTS: An increased neural response to errors at baseline predicted first-onset GAD over 1.5 years. The ERN was a significant predictor independent of other prominent risk factors, including baseline anxiety and depression symptoms and parental lifetime psychiatric history. Jointly the ERN and social anxiety symptoms provided the greatest power for predicting first-onset GAD. CONCLUSIONS: This study provides evidence for the utility of the ERN as a biomarker of risk for GAD during a key developmental period.

Cortical thickness is not associated with current depression in a clinical treatment study.

BACKGROUND: Reduced cortical thickness is a candidate biological marker of depression, although findings are inconsistent. This could reflect analytic heterogeneity, such as use of region-wise cortical thickness based on the Freesurfer Desikan-Killiany (DK) atlas or surface-based morphometry (SBM). The Freesurfer Destrieux (DS) atlas (more, smaller regions) has not been utilized in depression studies. This could also reflect differential gender and age effects. METHODS: Cortical thickness was collected from 170 currently depressed adults and 52 never-depressed adults. Visually inspected and approved Freesurfer-generated surfaces were used to extract cortical thickness estimates according to the DK atlas (68 regions) and DS atlas (148 regions) for region-wise analysis (216 total regions) and for SBM. RESULTS: Overall, except for small effects in a few regions, the two region-wise approaches generally failed to discriminate depressed adults from nondepressed adults or current episode severity. Differential effects by age and gender were also rare and small in magnitude. Using SBM, depressed adults showed a significantly thicker cluster in the left supramarginal gyrus than nondepressed adults (P = 0.047) but there were no associations with current episode severity. CONCLUSIONS: Three analytic approaches (i.e., DK atlas, DS atlas, and SBM) converge on the notion that cortical thickness is a relatively weak discriminator of current depression status. Differential age and gender effects do not appear to represent key moderators. Robust associations with demographic factors will likely hinder translation of cortical thickness into a clinically useful biomarker. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. Hum Brain Mapp 38:4370-4385, 2017. © 2017 Wiley Periodicals, Inc.

Symptoms of psychosis in schizophrenia, schizoaffective disorder, and bipolar disorder: A comparison of African Americans and Caucasians in the Genomic Psychiatry Cohort.

Several studies have reported differences between African Americans and Caucasians in relative proportion of psychotic symptoms and disorders, but whether this reflects racial bias in the assessment of psychosis is unclear. The purpose of this study was to examine the distribution of psychotic symptoms and potential bias in symptoms assessed via semi-structured interview using a cohort of 3,389 African American and 5,692 Caucasian participants who were diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder. In this cohort, the diagnosis of schizophrenia was relatively more common, and the diagnosis of bipolar disorder and schizoaffective disorder-bipolar type was less relatively common, among African Americans than Caucasians. With regard to symptoms, relatively more African Americans than Caucasians endorsed hallucinations and delusions symptoms, and this pattern was striking among cases diagnosed with bipolar disorder and schizoaffective-bipolar disorder. In contrast, the relative endorsement of psychotic symptoms was more similar among cases diagnosed with schizophrenia and schizoaffective disorder-depressed type. Differential item function analysis revealed that African Americans with mild psychosis over-endorsed "hallucinations in any modality" and under-endorsed "widespread delusions" relative to Caucasians. Other symptoms did not show evidence of racial bias. Thus, racial bias in assessment of psychotic symptoms does not appear to explain differences in the proportion of symptoms between Caucasians and African Americans. Rather, this may reflect ascertainment bias, perhaps indicative of a disparity in access to services, or differential exposure to risk factors for psychosis by race. © 2015 Wiley Periodicals, Inc.

Inter-rater reliability of the PIPES tool: validation of a surgical capacity index for use in resource-limited settings.

INTRODUCTION: In response to the need for simple, rapid means of quantifying surgical capacity in low resource settings, Surgeons OverSeas (SOS) developed the personnel, infrastructure, procedures, equipment and supplies (PIPES) tool. The present investigation assessed the inter-rater reliability of the PIPES tool. METHODS: As part of a government assessment of surgical services in Santa Cruz, Bolivia, the PIPES tool was translated into Spanish and applied in interviews with physicians at 31 public hospitals. An additional interview was conducted with nurses at a convenience sample of 25 of these hospitals. Physician and nurse responses were then compared to generate an estimate of reliability. For dichotomous survey items, inter-rater reliability between physicians and nurses was assessed using the Cohen's kappa statistic and percent agreement. The Pearson correlation coefficient was used to assess agreement for continuous items. RESULTS: Cohen's kappa was 0.46 for infrastructure, 0.43 for procedures, 0.26 for equipment, and 0 for supplies sections. The median correlation coefficient was 0.91 for continuous items. Correlation was 0.79 for the PIPES index, and ranged from 0.32 to 0.98 for continuous response items. CONCLUSIONS: Reliability of the PIPES tool was moderate for the infrastructure and procedures sections, fair for the equipment section, and poor for supplies section when comparing surgeons' responses to nurses' responses-an extremely rigorous test of reliability. These results indicate that the PIPES tool is an effective measure of surgical capacity but that the equipment and supplies sections may need to be revised.

The Prospective Predictive Power of Parent-Reported Personality Traits and Facets in First-Onset Depression in Adolescent Girls.

Certain personality traits and facets are well-known risk factors that predict first-onset depression during adolescence. However, prior research predominantly relied on self-reported data, which has limitations as a source of personality information. Reports from close informants have the potential to increase the predictive power of personality on first-onsets of depression in adolescents. With easy access to adolescents' behaviors across settings and time, parents may provide important additional information about their children's personality. The same personality trait(s) and facet(s) rated by selves (mean age 14.4 years old) and biological parents at baseline were used to prospectively predict depression onsets among 442 adolescent girls during a 72-month follow-up. First, bivariate logistic regression was used to examine whether parent-reported personality measures predicted adolescent girls' depression onsets; then multivariate logistic regression was used to test whether parent reports provided additional predictive power above and beyond self-reports of same trait or facet. Parent-reported personality traits and facets predicted adolescents' depression onsets, similar to findings using self-reported data. After controlling for the corresponding self-report measures, parent-reported higher openness (at the trait level) and higher depressivity (at the facet-level) incrementally predicted first-onset of depression in the sample. Findings demonstrated additional variance contributed by parent-reported personality measures and validated a multi-informant approach in using personality to prospectively predict onsets of depression in adolescent girls.

Association of Neuromelanin-Sensitive MRI Signal With Lifetime Substance Use in Young Women.

OBJECTIVE: Midbrain dopamine function plays a key role in translational models of substance use disorders. Whether midbrain dopamine function is associated with substance use frequency and severity or reward function in 20-24 year-olds remains a critical gap in knowledge. The authors collected neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a validated index of lifetime dopamine function in the substantia nigra/ventral tegmentum area (SN-VTA) complex, to characterize altered dopamine function. METHOD: Midbrain NM-MRI contrast-to-noise ratio (CNR) was acquired in 135 20-24 year-olds (105 women and 30 men). A composite measure of cumulative substance use was derived from factor analysis of lifetime alcohol intoxications, lifetime cannabis use, use of nicotine in heaviest month, number of classes of drugs used, and ever meeting DSM-5 criteria for a SUD. Trait reward function was assessed by self-report. RESULTS: Cumulative substance use was significantly positively associated with NM-MRI CNR in a large area of the bilateral SN-VTA complex, an effect which was driven by women (who comprised most of the sample) and by voxels with greater NM-MRI CNR, including the ventral tegmentum area. NM-MRI CNR was not associated with individual differences in trait reward function. CONCLUSIONS: History of substance use is associated with greater NM signal in NM-rich areas of the midbrain, especially in women. Future longitudinal studies with repeated NM-MRI assessments, especially in younger cohorts and while including more men, are warranted to evaluate whether aberrant dopamine function predates, follows, or is modulated by substance use.

Neural Correlates of Metacognition Impairment in Opioid Addiction.

BACKGROUND: Individuals with substance use disorder show impaired self-awareness of ongoing behavior. This deficit suggests problems with metacognition, which has been operationalized in the cognitive neuroscience literature as the ability to monitor and evaluate the success of one's own cognition and behavior. However, the neural mechanisms of metacognition have not been characterized in a population with drug addiction. METHODS: Community samples of participants with opioid use disorder (OUD) (n = 27) and healthy control participants (n = 29) performed a previously validated functional magnetic resonance imaging metacognition task (perceptual decision-making task along with confidence ratings of performance). Measures of recent drug use and addiction severity were also acquired. RESULTS: Individuals with OUD had lower metacognitive sensitivity (i.e., disconnection between task performance and task-related confidence) than control individuals. Trial-by-trial analyses showed that this overall group difference was driven by (suboptimally) low confidence in participants with OUD during correct trials. In functional magnetic resonance imaging analyses, the task engaged an expected network of brain regions (e.g., rostrolateral prefrontal cortex and dorsal anterior cingulate/supplementary motor area, both previously linked to metacognition); group differences emerged in a large ventral anterior cluster that included the medial and lateral orbitofrontal cortex and striatum (higher activation in OUD). Trial-by-trial functional magnetic resonance imaging analyses showed group differences in rostrolateral prefrontal cortex activation, which further correlated with metacognitive behavior across all participants. Exploratory analyses suggested that the behavioral and neural group differences were exacerbated by recent illicit opioid use and unexplained by general cognition. CONCLUSIONS: With confirmation and extension of these findings, metacognition and its associated neural circuits could become new, promising therapeutic targets in addiction.

Error-related brain activity shapes the association between trait neuroticism and internalizing symptomatology in two tasks.

The current study examined how individual differences in error-related brain activity might moderate the association between high trait neuroticism and internalizing symptoms. Data were collected from a sample of high-achieving young adults (N = 188) as part of a larger study on risk versus resiliency for psychopathology. Participants completed two behavioral tasks to elicit the error-related negativity (ERN): an arrow Flanker task and a Go/No-Go task. Analyses were constrained to two internalizing symptom dimensions of checking behavior and irritability. Contrary to expectations, ERN amplitude was not related to symptom severity at the bivariate level. However, ERN amplitude moderated the association between trait neuroticism and symptoms of ill temper, such that the neuroticism-irritability association was strongest among individuals with a blunted ERN. In addition, this finding was relatively consistent across tasks and across two complementary methods of scoring the ERN, suggesting an effect of ERN variance that is shared between tasks and that is relatively robust regarding processing differences. In all, the current study represents the first attempt to investigate how the ERN interacts with trait neuroticism to predict transdiagnostic symptom dimensions in adulthood.

Imaging the Vesicular Acetylcholine Transporter in Schizophrenia: A Positron Emission Tomography Study Using [18F]-VAT.

BACKGROUND: Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [18F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition. METHODS: A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [18F]-VAT. Distribution volume (VT) for [18F]-VAT was derived for each region of interest, and group differences in VT were assessed with 2-sample t tests. Functional significance was explored through correlations between VT and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB). RESULTS: No group differences in [18F]-VAT VT were observed. However, within the SCZ group, psychosis symptom severity was positively associated with VT in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with VT in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex. CONCLUSIONS: In this initial study, the severity of 2 important features of SCZ-psychosis and working memory deficit-was strongly associated with [18F]-VAT VT in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets.