Screening for psychotic experiences and psychotic disorders in general psychiatric settings: a systematic review and meta-analysis.

Background: The absence of systematic screening for psychosis within general psychiatric services contribute to substantial treatment delays and poor long-term outcomes. We conducted a meta-analysis to estimate rates of psychotic experiences, clinical high-risk for psychosis syndrome (CHR-P), and psychotic disorders identified by screening treatment-seeking individuals to inform implementation recommendations for routine psychosis screening in general psychiatric settings. Methods: PubMed and Web of Science databases were searched to identify empirical studies that contained information on the point prevalence of psychotic experiences, CHR-P, or psychotic disorders identified by screening inpatient and outpatient samples aged 12-64 receiving general psychiatric care. Psychotic experiences were identified by meeting threshold scores on validated self-reported questionnaires, and psychotic disorders and CHR-P by gold-standard structured interview assessments. A meta-analysis of each outcome was conducted using the Restricted Maximum Likelihood Estimator method of estimating effect sizes in a random effects model. Results: 41 independent samples (k=36 outpatient) involving n=25,751 patients (58% female, mean age: 24.1 years) were included. Among a general psychiatric population, prevalence of psychotic experiences was 44.3% (95% CI: 35.8-52.8%; 28 samples, n=21,957); CHR-P was 26.4% (95% CI: 20.0-32.7%; 28 samples, n=14,395); and psychotic disorders was 6.6% (95% CI: 3.3-9.8%; 32 samples, n=20,371). Conclusions: High rates of psychotic spectrum illness in general psychiatric settings underscore need for secondary prevention with psychosis screening. These base rates can be used to plan training and resources required to conduct assessments for early detection, as well as build capacity in interventions for CHR-P and early psychosis in non-specialty mental health settings.

Uncovering and mitigating bias in large, automated MRI analyses of brain development.

Large, population-based MRI studies of adolescents promise transformational insights into neurodevelopment and mental illness risk 1,2. However, MRI studies of youth are especially susceptible to motion and other artifacts 3,4. These artifacts may go undetected by automated quality control (QC) methods that are preferred in high-throughput imaging studies, 5 and can potentially introduce non-random noise into clinical association analyses. Here we demonstrate bias in structural MRI analyses of children due to inclusion of lower quality images, as identified through rigorous visual quality control of 11,263 T1 MRI scans obtained at age 9-10 through the Adolescent Brain Cognitive Development (ABCD) Study6. Compared to the best-rated images (44.9% of the sample), lower-quality images generally associated with decreased cortical thickness and increased cortical surface area measures (Cohen's d 0.14-2.84). Variable image quality led to counterintuitive patterns in analyses that associated structural MRI and clinical measures, as inclusion of lower-quality scans altered apparent effect sizes in ways that increased risk for both false positives and negatives. Quality-related biases were partially mitigated by controlling for surface hole number, an automated index of topological complexity that differentiated lower-quality scans with good specificity at Baseline (0.81-0.93) and in 1,000 Year 2 scans (0.88-1.00). However, even among the highest-rated images, subtle topological errors occurred during image preprocessing, and their correction through manual edits significantly and reproducibly changed thickness measurements across much of the cortex (d 0.15-0.92). These findings demonstrate that inadequate QC of youth structural MRI scans can undermine advantages of large sample size to detect meaningful associations.

Development of a transdiagnostic, resilience-focused intervention for at-risk adolescents.

BACKGROUND: Environmental adversity and subclinical symptoms of psychopathology in adolescents increase their risk for developing a future psychiatric disorder, yet interventions that may prevent poor outcomes in these vulnerable adolescents are not widely available. AIMS: To develop and test the feasibility and acceptability of a prevention-focused program to enhance resilience in high-risk adolescents. METHOD: Adolescents with subclinical psychopathology living in a predominantly low-income, Latinx immigrant community were identified during pediatrician visits. A group-based intervention focused on teaching emotion recognition and regulation skills was piloted in three cohorts of adolescents (n = 11, 10, and 7, respectively), using a single arm design. The second and third iterations included sessions with parents. RESULTS: Eighty-eight percent of participants completed the program, which was rated as beneficial. Also, from baseline to end of treatment, there was a significant decrease in subclinical symptoms and a significant increase in the adolescents' positive social attribution bias (all p < 0.05). CONCLUSIONS: A resilience-focused intervention administered to high-risk adolescents was found to be feasible and acceptable to participants. Future work is needed to determine whether such a program can reduce the incidence of negative outcomes, such as the development of psychiatric disorders and related disability, in this population.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Bed nucleus of the stria terminalis and amygdala responses to unpredictable threat in children.

Substantial evidence from studies in humans suggests the amygdala is pivotal for anxiety. Findings from animal models and translational studies suggests the bed nucleus of the stria terminalis (BNST) is also critical for anxiety and the anticipation of unpredictable threat in adults. However, it remains unknown whether the BNST is involved in unpredictable threat anticipation in children. Forty-two 8-10-year-olds completed resting-state functional magnetic resonance imaging (fMRI) scans and an unpredictable threat fMRI task in which they were trained to associate cues with images. Intrinsic connectivity analyses were performed to establish functional BNST and amygdala networks. BNST and amygdala activation to cues and images was tested. Significant findings were followed by task-based functional connectivity analyses. Children showed evidence for BNST and amygdala intrinsic connectivity that was similar to previous patterns observed in adults. In response to unpredictable cues relative to neutral face cues, children had a significant amygdala response but no response in the BNST. The amygdala, but not the BNST, also showed a significantly greater response to fear face images relative to neutral images. Thus, unpredictable threat activated the amygdala, but not BNST, in children. This finding is contrary to studies showing robust BNST activation to unpredictable threat in adults and may suggest that the BNST's role in threat processing emerges later in development.

Social anxiety is associated with BNST response to unpredictability.

BACKGROUND: Anxiety disorders are highly prevalent and cause substantial suffering and impairment. Whereas the amygdala has well-established contributions to anxiety, evidence from rodent and nonhuman primate models suggests that the bed nucleus of the stria terminalis (BNST) may play a critical, and possibly distinct, role in human anxiety disorders. The BNST mediates hypervigilance and anticipatory anxiety in response to an unpredictable or ambiguous threat, core symptoms of social anxiety, yet little is known about the BNST's role in social anxiety. METHODS: Functional magnetic resonance imaging was used to measure neural responses during a cued anticipation task with an unpredictable, predictable threat, and predictable neutral cues followed by threat or neutral images. Social anxiety was examined using a dimensional approach (N = 44 adults). RESULTS: For unpredictable cues, higher social anxiety was associated with lower BNST-amygdala connectivity. For unpredictable images, higher social anxiety was associated with greater connectivity between the BNST and both the ventromedial prefrontal cortex and the posterior cingulate cortex and lower connectivity between the BNST and postcentral gyrus. Social anxiety moderated the BNST-amygdala dissociation for unpredictable images; higher social anxiety was associated with BNST > amygdala response to unpredictable threat relative to unpredictable neutral images. CONCLUSIONS: Social anxiety was associated with alterations in BNST responses to unpredictability, particularly in the BNST's interactions with other brain regions, including the amygdala and prefrontal cortex. To our knowledge, these findings provide the first evidence for the BNST's role in social anxiety, which may be a potential new target for prevention and intervention.

Neurocircuitry underlying risk and resilience to social anxiety disorder.

BACKGROUND: Almost half of children with an inhibited temperament will develop social anxiety disorder by late adolescence. Importantly, this means that half of children with an inhibited temperament will not develop social anxiety disorder. Studying adults with an inhibited temperament provides a unique opportunity to identify neural signatures of both risk and resilience to social anxiety disorder. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure brain activation during the anticipation of viewing fear faces in 34 young adults (17 inhibited, 17 uninhibited). To identify neural signatures of risk, we tested for group differences in functional activation and connectivity in regions implicated in social anxiety disorder, including the prefrontal cortex, amygdala, and insula. To identify neural signatures of resilience, we tested for correlations between brain activation and both emotion regulation and social anxiety scores. RESULTS: Inhibited subjects had greater activation of a prefrontal network when anticipating viewing fear faces, relative to uninhibited subjects. No group differences were identified in the amygdala. Inhibited subjects had more negative connectivity between the rostral anterior cingulate cortex (ACC) and the bilateral amygdala. Within the inhibited group, those with fewer social anxiety symptoms and better emotion regulation skills had greater ACC activation and greater functional connectivity between the ACC and amygdala. CONCLUSIONS: These findings suggest that engaging regulatory prefrontal regions during anticipation may be a protective factor, or putative neural marker of resilience, in high-risk individuals. Cognitive training targeting prefrontal cortex function may provide protection against anxiety, especially in high-risk individuals, such as those with inhibited temperament.

Structural and functional bases of inhibited temperament.

Children born with an inhibited temperament are at heightened risk for developing anxiety, depression and substance use. Inhibited temperament is believed to have a biological basis; however, little is known about the structural brain basis of this vulnerability trait. Structural MRI scans were obtained from 84 (44 inhibited, 40 uninhibited) young adults. Given previous findings of amygdala hyperactivity in inhibited individuals, groups were compared on three measures of amygdala structure. To identify novel substrates of inhibited temperament, a whole brain analysis was performed. Functional activation and connectivity were examined across both groups. Inhibited adults had larger amygdala and caudate volume and larger volume predicted greater activation to neutral faces. In addition, larger amygdala volume predicted greater connectivity with subcortical and higher order visual structures. Larger caudate volume predicted greater connectivity with the basal ganglia, and less connectivity with primary visual and auditory cortex. We propose that larger volume in these salience detection regions may result in increased activation and enhanced connectivity in response to social stimuli. Given the strong link between inhibited temperament and risk for psychiatric illness, novel therapeutics that target these brain regions and related neural circuits have the potential to reduce rates of illness in vulnerable individuals.

Amygdala-cingulate intrinsic connectivity is associated with degree of social inhibition.

The tendency to approach or avoid novel people is a fundamental human behavior and is a core dimension of social anxiety. Resting state fMRI was used to test for an association between social inhibition and intrinsic connectivity in 40 young adults ranging from low to high in social inhibition. Higher levels of social inhibition were associated with specific patterns of reduced amygdala-cingulate cortex connectivity. Connectivity was reduced between the superficial amygdala and the rostral cingulate cortex and between the centromedial amygdala and the dorsal anterior cingulate cortex. Social inhibition also modulated connectivity in several well-established intrinsic networks; higher social inhibition correlated with reduced connectivity with default mode and dorsal attention networks and enhanced connectivity in salience and executive control networks. These findings provide important preliminary evidence that social inhibition reflects differences in the underlying intrinsic connectivity of the brain in the absence of social stimuli or stressors.

BNST neurocircuitry in humans.

Anxiety and addiction disorders are two of the most common mental disorders in the United States, and are typically chronic, disabling, and comorbid. Emerging evidence suggests the bed nucleus of the stria terminalis (BNST) mediates both anxiety and addiction through connections with other brain regions, including the amygdala and nucleus accumbens. Although BNST structural connections have been identified in rodents and a limited number of structural connections have been verified in non-human primates, BNST connections have yet to be described in humans. Neuroimaging is a powerful tool for identifying structural and functional circuits in vivo. In this study, we examined BNST structural and functional connectivity in a large sample of humans. The BNST showed structural and functional connections with multiple subcortical regions, including limbic, thalamic, and basal ganglia structures, confirming structural findings in rodents. We describe two novel connections in the human brain that have not been previously reported in rodents or non-human primates, including a structural connection with the temporal pole, and a functional connection with the paracingulate gyrus. The findings of this study provide a map of the BNST's structural and functional connectivity across the brain in healthy humans. In large part, the BNST neurocircuitry in humans is similar to the findings from rodents and non-human primates; however, several connections are unique to humans. Future explorations of BNST neurocircuitry in anxiety and addiction disorders have the potential to reveal novel mechanisms underlying these disabling psychiatric illnesses.

Behavioral inhibition and risk for developing social anxiety disorder: a meta-analytic study.

OBJECTIVE: Behavioral inhibition (BI) has been associated with increased risk for developing social anxiety disorder (SAD); however, the degree of risk associated with BI has yet to be systematically examined and quantified. The goal of the present study was to quantify the association between childhood BI and risk for developing SAD. METHOD: A comprehensive literature search was conducted to identify studies that assessed both BI and SAD. Meta-analyses were performed to estimate the odds ratio (OR) of the association between BI and SAD in children. RESULTS: Seven studies met inclusion criteria. BI was associated with a greater than sevenfold increase in risk for developing SAD (odds ratio = 7.59, p < .00002). This association remained significant even after considering study differences in temperament assessment, control group, parental risk, age at temperament assessment, and age at anxiety diagnosis. CONCLUSIONS: Identifying early developmental risk factors is critical for preventing psychiatric illness. Given that 15% of all children show extreme BI, and that almost half of these inhibited children will eventually develop SAD, we propose that BI is one of the largest single risk factors for developing SAD.

Expectation and temperament moderate amygdala and dorsal anterior cingulate cortex responses to fear faces.

A chronic tendency to avoid novelty is often the result of a temperamental bias called inhibited temperament, and is associated with increased risk for anxiety disorders. Neuroimaging studies have demonstrated that an inhibited temperament is associated with increased amygdalar blood-oxygenation-level-dependent (BOLD) response to unfamiliar faces that were not expected; however, the effects of variations in expectancy remain unknown. Using functional magnetic resonance imaging (fMRI), we studied BOLD response to infrequently encountered fear faces that were either expected or not expected in 42 adults with an inhibited or an uninhibited temperament. Individuals with an inhibited temperament had greater amygdala, but less dorsal anterior cingulate cortex (dACC), BOLD response when the stimuli were expected. In contrast, those with an uninhibited temperament had a smaller amygdala but larger dorsal anterior cingulate cortex BOLD response when expecting to see fear faces. These findings demonstrate temperament differences in expectancy effects and provide preliminary evidence for the dACC as a neural substrate mediating differences in inhibited temperament. Enhanced amygdala sensitivity coupled with weak inhibitory control from the dACC may form a neural circuit mediating behaviors characteristic of inhibited temperament and risk for anxiety disorders.

Manual MRI parcellation of the frontal lobe.

The ability to examine associations between neuropsychiatric conditions and functionally relevant frontal lobe sub-regions is a fundamental goal in neuropsychiatry, but methods for identifying frontal sub-regions in MR (magnetic resonance) images are not well established. Prior published techniques have principally defined gyral regions that do not necessarily correspond to known functional divisions. We present a method in which sulcal-gyral landmarks are used to manually delimit functionally relevant regions within the frontal lobe: primary motor cortex, anterior cingulate, deep white matter, premotor cortex regions (supplementary motor complex (SMC), frontal eye field and lateral premotor cortex) and prefrontal cortex (PFC) regions (medial PFC, dorsolateral PFC (DLPFC), inferior PFC, lateral orbitofrontal cortex (OFC) and medial OFC). Feasibility was tested by applying the protocol to brain MR data from 15 boys with attention-deficit/hyperactivity disorder (ADHD) and 15 typically developing controls, 8-12 years old. Intra- and inter-rater intraclass correlation coefficients were calculated using parcellation volumes from a subset of that group. Inter-rater results for the 22 hemisphere specific sub-regions ranged from 0.724 to 0.997, with all but seven values above 0.9. Boys with ADHD showed significantly smaller left hemisphere SMC and DLPFC volumes after normalization for total cerebral volume. These findings support the method as a reliable and valid technique for parcellating the frontal lobe into functionally relevant sub-regions.