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.

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.

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.

Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = -0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = -0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.

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.

Altered temporal, but intact spatial, features of transient network dynamics in psychosis.

Contemporary models of psychosis suggest that a continuum of severity of psychotic symptoms exists, with subthreshold psychotic experiences (PEs) potentially reflecting some genetic and environmental risk factors shared with clinical psychosis. Thus, identifying abnormalities in brain activity that manifest across this continuum can shed new light on the pathophysiology of psychosis. Here, we investigated the moment-to-moment engagement of brain networks ("states") in individuals with schizophrenia (SCZ) and PEs and identified features of these states that are associated with psychosis-spectrum symptoms. Transient brain states were defined by clustering "single snapshots" of blood oxygen level-dependent images, based on spatial similarity of the images. We found that individuals with SCZ (n = 35) demonstrated reduced recruitment of three brain states compared to demographically matched healthy controls (n = 35). Of these three illness-related states, one specific state, involving primarily the visual and salience networks, also occurred at a lower rate in individuals with persistent PEs (n = 22), compared to demographically matched healthy youth (n = 22). Moreover, the occurrence rate of this marker brain state was negatively correlated with the severity of PEs (r = -0.26, p = 0.003, n = 130). In contrast, the spatial map of this state appeared to be unaffected in the SCZ or PE groups. Thus, reduced engagement of a brain state involving the visual and salience networks was demonstrated across the psychosis continuum, suggesting that early disruptions of perceptual and affective function may underlie some of the core symptoms of the illness.

Increased amygdala-visual cortex connectivity in youth with persecutory ideation.

BACKGROUND: Subclinical delusional ideas, including persecutory beliefs, in otherwise healthy individuals are heritable symptoms associated with increased risk for psychotic illness, possibly representing an expression of one end of a continuum of psychosis severity. The identification of variation in brain function associated with these symptoms may provide insights about the neurobiology of delusions in clinical psychosis. METHODS: A resting-state functional magnetic resonance imaging scan was collected from 131 young adults with a wide range of severity of subclinical delusional beliefs, including persecutory ideas. Because of evidence for a key role of the amygdala in fear and paranoia, resting-state functional connectivity of the amygdala was measured. RESULTS: Connectivity between the amygdala and early visual cortical areas, including striate cortex (V1), was found to be significantly greater in participants with high (n = 43) v. low (n = 44) numbers of delusional beliefs, particularly in those who showed persistence of those beliefs. Similarly, across the full sample, the number of and distress associated with delusional beliefs were positively correlated with the strength of amygdala-visual cortex connectivity. Moreover, further analyses revealed that these effects were driven by those who endorsed persecutory beliefs. CONCLUSIONS: These findings are consistent with the hypothesis that aberrant assignments of threat to sensory stimuli may lead to the downstream development of delusional ideas. Taken together with prior findings of disrupted sensory-limbic coupling in psychosis, these results suggest that altered amygdala-visual cortex connectivity could represent a marker of psychosis-related pathophysiology across a continuum of symptom severity.

The Shared Genetic Basis of Educational Attainment and Cerebral Cortical Morphology.

Individual differences in educational attainment are linked to differences in intelligence, and predict important social, economic, and health outcomes. Previous studies have found common genetic factors that influence educational achievement, cognitive performance and total brain volume (i.e., brain size). Here, in a large sample of participants from the UK Biobank, we investigate the shared genetic basis between educational attainment and fine-grained cerebral cortical morphological features, and associate this genetic variation with a related aspect of cognitive ability. Importantly, we execute novel statistical methods that enable high-dimensional genetic correlation analysis, and compute high-resolution surface maps for the genetic correlations between educational attainment and vertex-wise morphological measurements. We conduct secondary analyses, using the UK Biobank verbal-numerical reasoning score, to confirm that variation in educational attainment that is genetically correlated with cortical morphology is related to differences in cognitive performance. Our analyses relate the genetic overlap between cognitive ability and cortical thickness measurements to bilateral primary motor cortex as well as predominantly left superior temporal cortex and proximal regions. These findings extend our understanding of the neurobiology that connects genetic variation to individual differences in educational attainment and cognitive performance.

Neural correlates of personal space intrusion.

A parietal-frontal network in primates is thought to support many behaviors occurring in the space around the body, including interpersonal interactions and maintenance of a particular "comfort zone" or distance from other people ("personal space"). To better understand this network in humans, we used functional MRI to measure the responses to moving objects (faces, cars, simple spheres) and the functional connectivity of two regions in this network, the dorsal intraparietal sulcus (DIPS) and the ventral premotor cortex (PMv). We found that both areas responded more strongly to faces that were moving toward (vs away from) subjects, but did not show this bias in response to comparable motion in control stimuli (cars or spheres). Moreover, these two regions were functionally interconnected. Tests of activity-behavior associations revealed that the strength of DIPS-PMv connectivity was correlated with the preferred distance that subjects chose to stand from an unfamiliar person (personal space size). In addition, the magnitude of DIPS and PMv responses was correlated with the preferred level of social activity. Together, these findings suggest that this parietal-frontal network plays a role in everyday interactions with others.

College students with depressive symptoms with and without fatigue: Differences in functioning, suicidality, anxiety, and depressive severity.

BACKGROUND: We examined whether fatigue was associated with greater symptomatic burden and functional impairment in college students with depressive symptoms. METHODS: Using data from the self-report Beck Depression Inventory (BDI), we stratified a group of 287 students endorsing significant symptoms of depression (BDI score ≥ 13) into 3 levels: no fatigue, mild fatigue, or moderate/severe fatigue. We then compared the 3 levels of fatigue across a battery of psychiatric and functional outcome measures. RESULTS: Approximately 87% of students endorsed at least mild fatigue. Students with moderate/severe fatigue had significantly greater depressive symptom severity compared with those with mild or no fatigue and scored higher on a suicide risk measure than those with mild fatigue. Students with severe fatigue evidenced greater frequency and intensity of anxiety than those with mild or no fatigue. Reported cognitive and functional impairment increased significantly as fatigue worsened. CONCLUSIONS: Depressed college students with symptoms of fatigue demonstrated functional impairment and symptomatic burden that worsened with increasing levels of fatigue. Assessing and treating symptoms of fatigue appears warranted within this population.

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.

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.

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.

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.

fMRI analysis of contrast polarity in face-selective cortex in humans and monkeys.

Recognition is strongly impaired when the normal contrast polarity of faces is reversed. For instance, otherwise-familiar faces become very difficult to recognize when viewed as photographic negatives. Here, we used fMRI to demonstrate related properties in visual cortex: 1) fMRI responses in the human Fusiform Face Area (FFA) decreased strongly (26%) to contrast-reversed faces across a wide range of contrast levels (5.3-100% RMS contrast), in all subjects tested. In a whole brain analysis, this contrast polarity bias was largely confined to the Fusiform Face Area (FFA; p<0.0001), with possible involvement of a left occipital face-selective region. 2) It is known that reversing facial contrast affects three image properties in parallel (absorbance, shading, and specular reflection). Here, comparison of FFA responses to those in V1 suggests that the contrast polarity bias is produced in FFA only when all three component properties were reversed simultaneously, which suggests a prominent non-linearity in FFA processing. 3) Across a wide range (180°) of illumination source angles, 3D face shapes without texture produced response constancy in FFA, without a contrast polarity bias. 4) Consistent with psychophysics, analogous fMRI biases for normal contrast polarity were not produced by non-face objects, with image statistics similar to the face stimuli. 5) Using fMRI, we also demonstrated a contrast polarity bias in awake behaving macaque monkeys, in the cortical region considered homologous to human FFA. Thus common cortical mechanisms may underlie facial contrast processing across ~25 million years of primate evolution.

Factors that distinguish college students with depressive symptoms with and without suicidal thoughts.

BACKGROUND: Suicide among college students is a significant public health concern. Although suicidality is linked to depression, not all depressed college students experience suicidal ideation (SI). The primary aim of this study was to determine potential factors that may distinguish college students with depressive symptoms with and without SI. METHODS: A total of 287 undergraduate college students with substantial depressive symptoms (Beck Depression Inventory [BDI] total score >13) with and without SI were compared across psychiatric and functional outcome variables. Independent sample t tests were conducted for each outcome variable using the suicide item of the BDI as a dichotomous (ie, zero vs nonzero score) grouping variable. RESULTS: Relative to students with substantial depressive symptoms without SI, those with SI were more symptomatic overall, having significantly higher levels of depressive symptoms, hopelessness, and anxiety. However, contrary to our expectations, nonsuicidal and suicidal students did not differ on measures of everyday functioning (ie, cognitive and physical functioning and grade point average). CONCLUSIONS: Our findings suggest that SI among college students is associated with increased subjective distress but may not adversely impact physical or cognitive functioning or academic performance.

Incentive salience: novel treatment strategies for major depression.

This article proposes that a recent shift in our understanding of dopamine function may support translational research to target deficits in positive emotions and reward processing in individuals with major depressive disorder (MDD). We review how dopamine functions to modulate approach behaviors in response to positive incentives, and we describe the incentive salience hypothesis, which posits that dopamine primarily modulates "wanting," or anticipatory reward, rather than "liking," or subjective pleasure. Although the incentive salience hypothesis was first proposed to help explain how drugs of abuse may reinforce harmful behaviors in the absence of continued pleasure or "liking," it may also provide a basis for understanding and developing new treatment approaches for MDD. Specifically, it provides a rationale for combining behaviorally activating psychotherapies and pro-dopaminergic agents to target impaired reward processing in MDD.

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.

Lower-level stimulus features strongly influence responses in the fusiform face area.

An intriguing region of human visual cortex (the fusiform face area; FFA) responds selectively to faces as a general higher-order stimulus category. However, the potential role of lower-order stimulus properties in FFA remains incompletely understood. To clarify those lower-level influences, we measured FFA responses to independent variation in 4 lower-level stimulus dimensions using standardized face stimuli and functional Magnetic Resonance Imaging (fMRI). These dimensions were size, position, contrast, and rotation in depth (viewpoint). We found that FFA responses were strongly influenced by variations in each of these image dimensions; that is, FFA responses were not "invariant" to any of them. Moreover, all FFA response functions were highly correlated with V1 responses (r = 0.95-0.99). As in V1, FFA responses could be accurately modeled as a combination of responses to 1) local contrast plus 2) the cortical magnification factor. In some measurements (e.g., face size or a combinations of multiple cues), the lower-level variations dominated the range of FFA responses. Manipulation of lower-level stimulus parameters could even change the category preference of FFA from "face selective" to "object selective." Altogether, these results emphasize that a significant portion of the FFA response reflects lower-level visual responses.