Validation of an ICD-Code-Based Case Definition for Psychotic Illness Across Three Health Systems.

BACKGROUND AND HYPOTHESIS: Psychosis-associated diagnostic codes are increasingly being utilized as case definitions for electronic health record (EHR)-based algorithms to predict and detect psychosis. However, data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. STUDY DESIGN: Using EHRs at 3 health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into 5 higher-order groups. 1133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. STUDY RESULTS: PPVs across all diagnostic groups and hospital systems exceeded 70%: Mass General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). CONCLUSIONS: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the case definitions used in the development of risk prediction models designed to predict or detect undiagnosed psychosis.

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.

Changes in responses of the amygdala and hippocampus during fear conditioning are associated with persecutory beliefs.

The persecutory delusion is the most common symptom of psychosis, yet its underlying neurobiological mechanisms are poorly understood. Prior studies have suggested that abnormalities in medial temporal lobe-dependent associative learning may contribute to this symptom. In the current study, this hypothesis was tested in a non-clinical sample of young adults without histories of psychiatric treatment (n = 64), who underwent classical Pavlovian fear conditioning while fMRI data were collected. During the fear conditioning procedure, participants viewed images of faces which were paired (the CS+) or not paired (the CS-) with an aversive stimulus (a mild electrical shock). Fear conditioning-related neural responses were measured in two medial temporal lobe regions, the amygdala and hippocampus, and in other closely connected brain regions of the salience and default networks. The participants without persecutory beliefs (n = 43) showed greater responses to the CS- compared to the CS+ in the right amygdala and hippocampus, while the participants with persecutory beliefs (n = 21) failed to exhibit this response. These between-group differences were not accounted for by symptoms of depression, anxiety or a psychosis risk syndrome. However, the severity of subclinical psychotic symptoms overall was correlated with the level of this aberrant response in the amygdala (p = .013) and hippocampus (p = .033). Thus, these findings provide evidence for a disruption of medial temporal lobe-dependent associative learning in young people with subclinical psychotic symptoms, specifically persecutory thinking.

Data-driven, connectome-wide analysis identifies psychosis-specific brain correlates of fear and anxiety.

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analysis may provide a complimentary, unbiased approach to identifying brain correlates of fear and anxiety. The aim of the current study was to identify the brain basis of fear and anxiety in early psychosis and controls using a data-driven approach. We analyzed data from the Human Connectome Project for Early Psychosis, a multi-site study of 125 people with psychosis and 58 controls with resting-state fMRI and clinical characterization. Multivariate pattern analysis of whole-connectome data was used to identify shared and psychosis-specific brain correlates of fear and anxiety using the NIH Toolbox Fear-Affect and Fear-Somatic Arousal scales. We then examined clinical correlations of Fear-Affect scores and connectivity patterns. Individuals with psychosis had higher levels of Fear-Affect scores than controls (p < 0.05). The data-driven analysis identified a cluster encompassing the amygdala and hippocampus where connectivity was correlated with Fear-Affect score (p < 0.005) in the entire sample. The strongest correlate of Fear-Affect was between this cluster and the anterior insula and stronger connectivity was associated with higher Fear-Affect scores (r = 0.31, p = 0.0003). The multivariate pattern analysis also identified a psychosis-specific correlate of Fear-Affect score between the amygdala/hippocampus cluster and a cluster in the ventromedial prefrontal cortex (VMPFC). Higher Fear-Affect scores were correlated with stronger amygdala/hippocampal-VMPFC connectivity in the early psychosis group (r = 0.33, p = 0.002), but not in controls (r = -0.15, p = 0.28). The current study provides evidence for the transdiagnostic role of the amygdala, hippocampus, and anterior insula in the neural basis of fear and anxiety and suggests a psychosis-specific relationship between fear and anxiety symptoms and amygdala/hippocampal-VMPFC connectivity. Our novel data-driven approach identifies novel, psychosis-specific treatment targets for fear and anxiety symptoms and provides complimentary evidence to decades of hypothesis-driven approaches examining the brain basis of threat processing.

Validation of an ICD-code-based case definition for psychotic illness across three health systems.

Background and Hypothesis: Early detection of psychosis is critical for improving outcomes. Algorithms to predict or detect psychosis using electronic health record (EHR) data depend on the validity of the case definitions used, typically based on diagnostic codes. Data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. Study Design: Using EHRs at three health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into five higher-order groups. 1,133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. Study Results: PPVs across all diagnostic groups and hospital systems exceeded 70%: Massachusetts General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). Conclusions: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the development of risk prediction models designed to predict or detect undiagnosed psychosis.

A Brief Resilience-Enhancing Intervention and Loneliness in At-Risk Young Adults: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial assesses whether a behavioral intervention focused on resilience is associated with feelings of loneliness among young adults.

Social Withdrawal, Loneliness, and Health in Schizophrenia: Psychological and Neural Mechanisms.

BACKGROUND AND HYPOTHESIS: Some of the most debilitating aspects of schizophrenia and other serious mental illnesses (SMI) are the impairments in social perception, motivation, and behavior that frequently accompany these conditions. These impairments may ultimately lead to chronic social disconnection (ie, social withdrawal, objective isolation, and perceived social isolation or loneliness), which may contribute to the poor cardiometabolic health and early mortality commonly observed in SMI. However, the psychological and neurobiological mechanisms underlying relationships between impairments in social perception and motivation and social isolation and loneliness in SMI remain incompletely understood. STUDY DESIGN: A narrative, selective review of studies on social withdrawal, isolation, loneliness, and health in SMI. STUDY RESULTS: We describe some of what is known and hypothesized about the psychological and neurobiological mechanisms of social disconnection in the general population, and how these mechanisms may contribute to social isolation and loneliness, and their consequences, in individuals with SMI. CONCLUSIONS: A synthesis of evolutionary and cognitive theories with the "social homeostasis" model of social isolation and loneliness represents one testable framework for understanding the dynamic cognitive and biological correlates, as well as the health consequences, of social disconnection in SMI. The development of such an understanding may provide the basis for novel approaches for preventing or treating both functional disability and poor physical health that diminish the quality and length of life for many individuals with these conditions.

Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar development.

Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence. We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data. In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores. Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood. These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood.

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.

Efficacy of a transdiagnostic, prevention-focused program for at-risk young adults: a waitlist-controlled trial.

BACKGROUND: Prevention programs that are 'transdiagnostic' may be more cost-effective and beneficial, in terms of reducing levels of psychopathology in the general population, than those focused on a specific disorder. This randomized controlled study evaluated the efficacy of one such intervention program called Resilience Training (RT). METHODS: College students who reported mildly elevated depressive or subclinical psychotic symptoms ('psychotic experiences' (PEs)) (n = 107) were randomized to receiving RT (n = 54) or to a waitlist control condition (n = 53). RT consists of a four-session intervention focused on improving resilience through the acquisition of mindfulness, self-compassion, and mentalization skills. Measures of symptoms and these resilience-enhancing skills were collected before and after the 4-week RT/waitlist period, with a follow-up assessment 12-months later. RESULTS: Compared to the waitlist control group, RT participants reported significantly greater reductions in PEs, distress associated with PEs, depression, and anxiety, as well as significantly greater improvements in resilience, mindfulness, self-compassion, and positive affect, following the 4-week RT/waitlist period (all p < 0.03). Moreover, improvements in resilience-promoting skills were significantly correlated with symptom reductions (all p < 0.05). Lastly, the RT-related reductions in PEs and associated distress were maintained at the 12-month follow-up assessment. CONCLUSIONS: RT is a brief, group-based intervention associated with improved resilience and reduced symptoms of psychopathology, with sustained effects on PEs, in transdiagnostically at-risk young adults. Follow-up studies can further assess the efficacy of RT relative to other interventions and test whether it can reduce the likelihood of developing a serious mental illness.

Interdigitated Columnar Representation of Personal Space and Visual Space in Human Parietal Cortex.

Personal space (PS) is the space around the body that people prefer to maintain between themselves and unfamiliar others. Intrusion into personal space evokes discomfort and an urge to move away. Physiologic studies in nonhuman primates suggest that defensive responses to intruding stimuli involve the parietal cortex. We hypothesized that the spatial encoding of interpersonal distance is initially transformed from purely sensory to more egocentric mapping within human parietal cortex. This hypothesis was tested using 7 Tesla (7T) fMRI at high spatial resolution (1.1 mm isotropic), in seven subjects (four females, three males). In response to visual stimuli presented at a range of virtual distances, we found two categories of distance encoding in two corresponding radially-extending columns of activity within parietal cortex. One set of columns (P columns) responded selectively to moving and stationary face images presented at virtual distances that were nearer (but not farther) than each subject's behaviorally-defined personal space boundary. In most P columns, BOLD response amplitudes increased monotonically and nonlinearly with increasing virtual face proximity. In the remaining P columns, BOLD responses decreased with increasing proximity. A second set of parietal columns (D columns) responded selectively to disparity-based distance cues (near or far) in random dot stimuli, similar to disparity-selective columns described previously in occipital cortex. Critically, in parietal cortex, P columns were topographically interdigitated (nonoverlapping) with D columns. These results suggest that visual spatial information is transformed from visual to body-centered (or person-centered) dimensions in multiple local sites within human parietal cortex.SIGNIFICANCE STATEMENT Recent COVID-related social distancing practices highlight the need to better understand brain mechanisms which regulate "personal space" (PS), which is defined by the closest interpersonal distance that is comfortable for an individual. Using high spatial resolution brain imaging, we tested whether a map of external space is transformed from purely visual (3D-based) information to a more egocentric map (related to personal space) in human parietal cortex. We confirmed this transformation and further showed that it was mediated by two mutually segregated sets of columns: one which encoded interpersonal distance and another that encoded visual distance. These results suggest that the cortical transformation of sensory-centered to person-centered encoding of space near the body involves short-range communication across interdigitated columns within parietal cortex.

Personal space increases during the COVID-19 pandemic in response to real and virtual humans.

Personal space is the distance that people tend to maintain from others during daily life in a largely unconscious manner. For humans, personal space-related behaviors represent one form of non-verbal social communication, similar to facial expressions and eye contact. Given that the changes in social behavior and experiences that occurred during the COVID-19 pandemic, including "social distancing" and widespread social isolation, may have altered personal space preferences, we investigated this possibility in two independent samples. First, we compared the size of personal space measured before the onset of the pandemic to its size during the pandemic in separate groups of subjects. Personal space size was significantly larger in those assessed during (compared to those assessed before) the onset of the pandemic (all d > 0.613, all p < 0.007). In an additional cohort, we measured personal space size, and discomfort in response to intrusions into personal space, longitudinally before and during the pandemic, using both conventional and virtual reality-based techniques. Within these subjects, we found that measurements of personal space size with respect to real versus virtual humans were significantly correlated with one another (r = 0.625-0.958) and similar in magnitude. Moreover, the size of personal space, as well as levels of discomfort during personal space intrusions, increased significantly during (compared to before) the COVID-19 pandemic in response to both real and virtual humans (all d > 0.842, all p < 0.01). Lastly, we found that the practice of social distancing and perceived (but not actual) risk of being infected with COVID-19 were linked to this personal space enlargement during the pandemic (all p < 0.038). Taken together, these findings suggest that personal space boundaries expanded during the COVID-19 pandemic independent of actual infection risk level. As the day-to-day effects of the pandemic subside, personal space preferences may provide one index of recovery from the psychological effects of this crisis.

Network hub centrality and working memory performance in schizophrenia.

Cognitive impairment, and working memory deficits in particular, are debilitating, treatment-resistant aspects of schizophrenia. Dysfunction of brain network hubs, putatively related to altered neurodevelopment, is thought to underlie the cognitive symptoms associated with this illness. Here, we used weighted degree, a robust graph theory metric representing the number of weighted connections to a node, to quantify centrality in cortical hubs in 29 patients with schizophrenia and 29 age- and gender-matched healthy controls and identify the critical nodes that underlie working memory performance. In both patients and controls, elevated weighted degree in the default mode network (DMN) was generally associated with poorer performance (accuracy and reaction time). Higher degree in the ventral attention network (VAN) nodes in the right superior temporal cortex was associated with better performance (accuracy) in patients. Degree in several prefrontal and parietal areas was associated with cognitive performance only in patients. In regions that are critical for sustained attention, these correlations were primarily driven by between-network connectivity in patients. Moreover, a cross-validated prediction analysis showed that a linear model using a summary degree score can be used to predict an individual's working memory accuracy (r = 0.35). Our results suggest that schizophrenia is associated with dysfunctional hubs in the cortical systems supporting internal and external cognition and highlight the importance of topological network analysis in the search of biomarkers for cognitive deficits in schizophrenia.

Neural Correlates of Variation in Personal Space and Social Functioning in Schizophrenia and Healthy Individuals.

BACKGROUND: Changes in the regulation of interpersonal distance, or "personal space" (PS), have been repeatedly observed in schizophrenia and, in some studies, linked to negative symptoms. However, the neurobiological basis of these impairments is poorly understood. METHODS: Personal space measurements, functional connectivity of a brain network sensitive to intrusions into PS, and symptoms of social withdrawal and anhedonia were assessed, and associations among these outcomes measured, in 33 individuals with a psychotic disorder (primarily schizophrenia [SCZ]) and 36 control subjects (CON). RESULTS: Personal space size was significantly higher (P = .002) and PS permeability (reflecting the capacity to tolerate intrusions into PS) was significantly lower (P = .021) in the SCZ relative to the CON group, and both measures were significantly correlated with social anhedonia and withdrawal in the full sample (all P < .007). Moreover, functional connectivity between the PS and default mode (DM) networks was significantly correlated with the permeability, but not the size, of PS in the full sample and in the SCZ and CON groups separately, and with social withdrawal in the SCZ group. Lastly, the association between PS-DM network connectivity and social withdrawal in the SCZ group was fully mediated by PS permeability. DISCUSSION: Neural and behavioral aspects of PS regulation are linked to social motivation in both healthy individuals and those with psychotic disorders, suggesting that measurements of PS could serve as transdiagnostic markers of social functioning.

Relationships among subclinical psychotic symptoms in young adults over time.

BACKGROUND: Subclinical psychotic symptoms are common in the general population and are often benign. However, those that become distressing or persistent may increase risk for the development of a psychotic disorder. Cognitive models have proposed that certain appraisals of hallucinatory experiences can lead to delusional beliefs, particularly if an individual is experiencing negative mood. However, the dynamic relationships among these symptoms are poorly understood. This study examined the longitudinal relationships among subclincal hallucinations, delusional ideation, and depression in a sample of young adults. METHODS: 677 college students completed baseline questionnaires to assess: delusional ideation (Peters Delusions Inventory), hallucinations (Launay-Slade Hallucinations Scale-Extended), and depression (Beck Depression Inventory). These measures were repeated 7, 13, 19, and 25 months later. RESULTS: Higher baseline severity of hallucinations was strongly predictive of severity of delusions across all future follow-up timepoints, specifically when baseline depression was high. However, the severity of hallucinations did not change over time, nor were they predicted by baseline delusional ideation. CONCLUSIONS: These findings support the proposal that hallucinations frequently precede more severe delusional ideation, rather than the reverse sequence, particularly when depressive symptoms are present. Such longitudinal relationships provide clues to the underlying mechanisms of psychosis, highlighting one pathway for intervention.

Diminished frontal pole size and functional connectivity in young adults with high suicidality.

BACKGROUND: Suicide rates among young people have been increasing in recent years, yet no validated methods are available for identifying those who are at greatest risk for suicide. Abnormalities in the medial prefrontal cortex have been previously observed in suicidal individuals, but confounding factors such as treatment and chronic illness may have contributed to these findings. Thus, in this study we tested whether the size of the medial prefrontal cortex is altered in suicidal young adults who have received no treatment with psychotropic medications. METHODS: Suicidality was evaluated using the Suicide Behaviors Questionnaire-Revised (SBQ-R) and surface areas of four regions-of-interest (ROIs) within the medial prefrontal cortex were measured using magnetic resonance imaging (MRI) in a cohort of college students (n = 102). In addition, a secondary seed-based functional connectivity analysis was conducted using resting-state functional MRI data. Areas and functional connectivity of the medial prefrontal cortex of young adults with high suicidality (HS; SBQ-R score > 7; n = 20) were compared to those with low suicidality (LS; SBQ-R score = 3, n = 37). RESULTS: Compared to the LS group, the HS group had a significantly lower surface area of the right frontal pole (p < 0.05, Bonferroni-corrected) and significantly lower functional connectivity of the right frontal pole with the bilateral inferior frontal cortex (p < 0.001, Monte-Carlo corrected). LIMITATION: These findings require replication in a larger sample and extension in younger (adolescent) populations. CONCLUSION: Diminished frontal pole surface area and functional connectivity may be linked to elevated levels of suicidality in young people.