Functional connectivity and glutamate levels of the medial prefrontal cortex in schizotypy are related to sensory amplification in a probabilistic reasoning task.

The circular inference (CI) computational model assumes a corruption of sensory data by prior information and vice versa, leading at the extremes to 'see what we expect' (through prior amplification) and/or to 'expect what we see' (through sensory amplification). Although a CI mechanism has been reported in a schizophrenia population, it has not been investigated in individuals experiencing psychosis-like experiences, such as people with high schizotypy traits. Furthermore, the neurobiological basis of CI, such as the link between hierarchical amplifications, excitatory neurotransmission, and resting state functional connectivity (RSFC), remains untested. The participants included in the present study consisted of a subsample of those recruited in a study previously published by our group, Kozhuharova et al. (2021b). We included 36 participants with High (n=18) and Low (n=18) levels of schizotypy who completed a probabilistic reasoning task (the Fisher task) for which individual confidence levels were obtained and fitted to the CI model. Participants also underwent a 1H-Magnetic Resonance Spectroscopy (MRS) scan to measure medial prefrontal cortex (mPFC) glutamate metabolite levels, and a functional Magnetic Resonance Imaging (fMRI) scan to measure RSFC of the medial prefrontal cortex (mPFC). People with high levels of schizotypy exhibited changes in CI parameters, altered cortical excitatory neurotransmission and RSFC that were all associated with sensory amplification. Our findings capture a multimodal signature of CI that is observable in people early in the psychosis spectrum.

Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

High levels of childhood trauma associated with changes in hippocampal functional activity and connectivity in young adults during novelty salience.

Childhood trauma (CT) has been linked to increased risk for psychosis. Moreover, CT has been linked to psychosis phenotypes such as impaired cognitive and sensory functions involved in the detection of novel sensory stimuli. Our objective was to investigate if CT was associated with changes in hippocampal and superior temporal gyrus functional activation and connectivity during a novelty detection task. Fifty-eight young adults were assigned to High-CT (n = 28) and Low-CT (n = 24) groups based on their scores on the childhood trauma questionnaire (CTQ) and underwent functional Magnetic Resonance Imaging during an auditory oddball task (AOT). Relative to the Low CT group, High CT participants showed reduced functional activation in the left hippocampus during the unpredictable tone condition of the AOT. Furthermore, in the High CT group, psychophysiological interaction analysis revealed hypoconnectivity between the hippocampus and temporal and medial regions. The present study indicates both altered hippocampal activation and hippocampal-temporal-prefrontal connectivity during novelty detection in individuals that experienced CT, similarly to that reported in psychosis risk populations. Early stressful experiences and environments may alter hippocampal function during salient events, mediating the relationship between childhood trauma and psychosis risk.

Longitudinal associations between self-reported attachment dimensions and neurostructural development from adolescence to early adulthood.

The existing literature suggests that individual differences in attachment may be associated with differential trajectories of structural brain development. In addition to maturation during infancy and childhood, developmental trajectories are characteristic of adolescence, a period marked by increasingly complex interpersonal relationships and significant neurostructural and functional plasticity. It remains to be examined whether attachment prospectively relates to neurostructural developmental trajectories during adolescence. In this longitudinal study, we investigated whether self-reported attachment dimensions of anxiety (AX) and avoidance (AV) could predict elements of cortical thickness (CT) and subcortical volume (SV) trajectories in 95 typically developing adolescents (12-19 years old at study baseline). Self-reported scores of AX and AV were obtained at study baseline, and neurostructural development was assessed at baseline and three timepoints over the four following years. Self-reported AX and AV were associated with steeper CT decreases in prefrontal cortical and cortical midline structures as well as anterior temporal cortex, particularly in participants younger at study baseline. Regarding SV, preliminary differential associations were observed between developmental trajectories and attachment dimensions. Our study suggests that interindividual differences in attachment contribute to shaping neurodevelopmental trajectories for several cortical and subcortical structures during adolescence and young adulthood.

A Developmental Study of Mirror-Gazing-Induced Anomalous Self-Experiences and Self-Reported Schizotypy from 7 to 28 Years of Age.

INTRODUCTION: The mirror-gazing task (MGT) is an experimental paradigm inducing anomalous perceptions and anomalous experiences of self-face (ASEs) in the general population, ranging from changes in light and color, to face deformation, to experiencing one's specular image as another identity. Subclinical ASEs have been related to the emergence of the risk for developing psychotic disorders, and inducing such states in the general population could shed light on the factors underlying interindividual differences in proneness to these phenomena. We aimed to examine the influence of schizotypal personality traits on proneness to experiencing induced ASEs from a developmental perspective, from childhood to adulthood. METHODS: Two hundred and sixteen children, adolescents, and young adults participated in the MGT, and their schizotypal personality traits were assessed with the Schizotypal Personality Questionnaire. Statistical analyses assessed the relationship between schizotypy dimensions and induced ASEs, and we further tested their dynamic relationship as function of age (from childhood to adulthood). RESULTS: Results confirmed the developmental trajectory of the different schizotypy dimensions, with scores peaking during adolescence, and proneness to induced ASEs seemed to follow a similar developmental trajectory. Moreover, positive (p = 0.001) and disorganized (p = 0.004) dimensions were found to contribute to the proneness to experiencing induced ASEs. Finally, the developmental model showed that positive schizotypy (p = 0.035) uniquely distinguished between experiencing other-identity phenomena between childhood and adulthood. CONCLUSION: This study has the potential to inform research on early detection of psychosis through a developmental approach and links the concept of schizotypy with processes of perceptual self-distortions.

Cortical thickness of the insula and prefrontal cortex relates to externalizing behavior: Cross-sectional and prospective findings.

Externalizing behaviors (EBs) pertain to a diverse set of aggressive, antisocial, and potentially destructive behaviors directed toward the external environment. They range from nonclinical to clinical in severity, associated with opposition, aggression, hyperactivity, or impulsivity, and are considered a risk factor for the emergence of psychopathology later in adulthood. Focusing on community adolescents (N = 102; 49 female and 53 male adolescents; age range 12-19 years), this study aimed to explore the relations between EBs and the cortical thickness of regions of interest as well as to identify possible risk markers that could improve understanding of the EB construct. Using a mixed cross-sectional and prospective design (1-year follow-up), we report specific associations with cortical thickness of the left insular, right orbitofrontal, and left anterior cingulate cortex. Specifically, thinner left insular and right orbitofrontal cortex was associated with higher EBs, and thinner left anterior cingulate cortex predicted less reduction in EBs 1 year later. In addition, further examination of the aggression and rule-breaking subscales of the Youth/Adult Self-Report, used to assess EBs, revealed specific associations with insular subregions. Findings suggest that cortical structure morphology may significantly relate to the expression and maintenance of EBs within the general population of adolescents.

The continuum of attention dysfunction: Evidence from dynamic functional network connectivity analysis in neurotypical adolescents.

The question of whether attention-related disorders such as attention-deficit/hyperactivity disorder (ADHD) are best understood as clinical categories or as extreme ends of a spectrum is an ongoing debate. Assessing individuals with varying degrees of attention problems and utilizing novel methodologies to assess relationships between attention and brain activity may provide key information to support the spectrum hypothesis. We scanned 91 neurotypical adolescents during rest using functional magnetic resonance imaging. We conducted static and dynamic functional network connectivity (FNC) analysis and correlated findings to behavioral metrics of ADHD, attention problems, and impulsivity. We found that dynamic FNC analysis detects significant differences in large-scale neural connectivity as a function of individual differences in attention and impulsivity that are obscured in static analysis. We show ADHD manifestations and attention problems are associated with diminished Salience Network-centered FNC and that ADHD manifestations and impulsivity are associated with prolonged periods of dynamically hyperconnected states. Importantly, our meta-state analysis results reveal a relationship between ADHD manifestations and exhibiting variable and volatile dynamic behavior such as changing meta-states more often and traveling over a greater dynamic range. These findings in non-clinical adolescents provide support for the continuum model of attention disorders.

Associations of resting-state perfusion and auditory verbal hallucinations with and without emotional content in schizophrenia.

Auditory Verbal Hallucinations (AVH) are highly prevalent in patients with schizophrenia. AVH with high emotional content lead to particularly poor functional outcome. Increasing evidence shows that AVH are associated with alterations in structure and function in language and memory related brain regions. However, neural correlates of AVH with emotional content remain unclear. In our study (n = 91), we related resting-state cerebral perfusion to AVH and emotional content, comparing four groups: patients with AVH with emotional content (n = 13), without emotional content (n = 14), without hallucinations (n = 20) and healthy controls (n = 44). Patients with AVH and emotional content presented with increased perfusion within the amygdala and the ventromedial and dorsomedial prefrontal cortex (vmPFC/ dmPFC) compared to patients with AVH without emotional content. In addition, patients with any AVH showed hyperperfusion within the anterior cingulate gyrus, the vmPFC/dmPFC, the right hippocampus, and the left pre- and postcentral gyrus compared to patients without AVH. Our results indicate metabolic alterations in brain areas critical for the processing of emotions as key for the pathophysiology of AVH with emotional content. Particularly, hyperperfusion of the amygdala may reflect and even trigger emotional content of AVH, while hyperperfusion of the vmPFC/dmPFC cluster may indicate insufficient top-down amygdala regulation in patients with schizophrenia.

The role of mentalizing in the relationship between schizotypal personality traits and state signs of psychosis risk captured by cognitive and perceptive basic symptoms.

Objective: Schizotypal traits and disturbances in mentalizing (the capacity to understand the mental states driving one's own and others' behaviors) have been implicated in increased vulnerability for psychosis. Therefore, we explored the associations linking schizotypal traits, mentalizing difficulties and their interactions to clinical high-risk for psychosis (CHR-P), as captured by the Basic Symptoms (BS) approach, during adolescence and young adulthood. Methods: Eighty-seven adolescents and young adults from the general population (46% male, 44% female; age: 14-23 years) were assessed with the Schizophrenia Proneness Interview (SPI-CY/A) for 11 perceptive and cognitive BS, with the Schizotypal Personality Questionnaire (SPQ) for schizotypal traits, and with the Reflective Functioning Questionnaire (RFQ) for self-reported mentalizing abilities. The RFQ evaluates the level of certainty (RFQc scale) and uncertainty (RFQu scale) with which individuals use mental state information to explain their own and others' behaviors. Results: Logistic regression models showed significant positive effects of the SPQ disorganization scale on perceptive BS and of the SPQ interpersonal scale on cognitive BS. Post-hoc analyses revealed that schizotypal features pertaining to odd speech and social anxiety, respectively, were associated with perceptive and cognitive BS. Furthermore, higher scores on the RFQu scale and lower scores on the RFQc scale independently explained the presence of cognitive BS. Finally, significant interaction effects between RFQc and SPQ odd speech on perceptive BS, and between RFQc and SPQ social anxiety on cognitive BS were found. Conclusion: Our findings suggest that schizotypal traits and mentalizing significantly relate both independently and through their interactions to the presence of cognitive and perceptive BS included in CHR-P criteria. Furthermore, mentalizing dysfunction may contribute in the relation between schizotypal traits and early state signs of CHR-P. Mentalizing may support both detection and early treatment of CHR-P among adolescents and young adults who present with trait risk for psychosis.

Developmental Trajectories of Cortical Thickness in Relation to Schizotypy During Adolescence.

Investigating potential gray matter differences in adolescents presenting higher levels of schizotypy personality traits could bring further insights into the development of schizophrenia spectrum disorders. Research has yet to examine the morphological correlates of schizotypy features during adolescence prospectively, and no information is available on the developmental trajectories from adolescence to adulthood. We employed mixed model regression analysis to investigate developmental trajectories of cortical thickness (CT) in relation to schizotypy dimensions in a cohort of 109 adolescents from the general population for whom MRI-scans were acquired over a 5-year period, culminating in a total of 271 scans. Structural data were processed with FreeSurfer software, statistical analyses were conducted using mixed regression models following a ROI-based approach, and schizotypy was assessed with the Schizotypal Personality Questionnaire (SPQ). Accelerated thinning was observed in the posterior cingulate cortex in relation to high levels of positive schizotypy, whereas high levels of disorganized schizotypy were associated with a similar trajectory pattern in the anterior cingulate cortex. The developmental course of CT in the prefrontal, occipital, and cingulate cortices differed between adolescents expressing higher vs lower levels of negative schizotypy. Participants reporting high scores on all schizotypy dimensions were associated with differential trajectories of CT in posterior cingulate cortex and occipital cortex. Consistently with prospective developmental studies of clinical risk conversion, the negative schizotypy dimension appears to constitute the most informative dimension for psychosis-related psychopathology, as its cerebral correlates in adolescents most closely overlap with results found in clinical high risk for psychosis studies.

Developmental trajectories of subcortical structures in relation to dimensional schizotypy expression along adolescence.

Morphological abnormalities of subcortical structures have been consistently reported along the schizophrenia clinical spectrum, and they may play an important role in the pathophysiology of psychosis. However, the question arises whether these subcortical features are consequences of medication and illness chronicity, or if they contribute to the vulnerability to develop schizophrenia spectrum disorders. If some of the subcortical abnormalities could be evidenced in community adolescents expressing higher schizotypal traits (psychometric schizotypy), they could potentially shed light on vulnerability markers. To date, very few studies have examined the link between psychometric schizotypy and volumes of subcortical regions, and none of them have used a longitudinal design. This study sets out to investigate developmental trajectories of subcortical volumes in 110 community adolescents (12 to 20 years old), for whom MRI-scans were acquired over a period of 5 years, reaching a total of 297 scans. Analyses were conducted using Freesurfer, and schizotypal traits were measured with the Schizotypal Personality Questionnaire (SPQ). Using mixed model regression analyses following a region-of-interest approach, we observed differential linear developmental trajectories in four subcortical structures when comparing higher versus lower scorers on the disorganized schizotypy dimension (bilateral hippocampus, left-lateral ventricle and left-pallidum) and the negative schizotypy dimension (bilateral pallidum, and right-thalamus). All results survived a threshold of p < .05 (FDR-corrected) while covarying for the effect of other psychological problems (externalized and internalized psychopathology). These results indicate that expression of higher levels of negative and disorganized schizotypy during adolescence was associated with neural markers linking schizotypy personality features to schizophrenia spectrum disorders.

Resting-State Networks of Adolescents Experiencing Depersonalization-Like Illusions: Cross-sectional and Longitudinal Findings.

The mirror-gazing task (MGT) experimentally induces illusions, ranging from simple color changes in the specular image of oneself, to depersonalization-like anomalous self-experiences (ASE) as in experiencing one's specular image as someone else. The objective was to characterize how connectivity in resting-state networks (RSNs) differed in adolescents reporting such depersonalization-like ASEs during the MGT, in a cross-sectional (Y1) and in a longitudinal manner (a year after). 75 adolescents were recruited; for the cross-sectional analysis, participants were split into 2 groups: those who reported depersonalization-like ASEs on the MGT (ASE), and those who did not (NoASE). For the longitudinal analysis, participants were split into 3 groups whether they experienced MGT depersonalization-like ASEs: only at Y1 (Remitters), both times (Persisters), or never (Controls). Participants also filled out self-reports assessing schizotypal personality (Schizotypal Personality Questionnaire [SPQ]), and underwent resting-state functional MRI procedure (rs-fMRI). A group level Independent Component Analysis (ICA) was conducted and voxel-wise inter-group differences within RSNs were examined. The rs-fMRI analysis revealed lower connectivity of specific visual areas within the primary visual network (PVN), and higher connectivity of regions within the Default Mode Network (DMN) when contrasting the ASE and NoASE groups. The areas that were atypically connected within the PVN further presented differential pattern of connectivity in the longitudinal analysis. Atypical connectivity of visual area within the DMN at Y1 was associated with higher scores on the disorganized dimension of schizotypy at the second evaluation. The present study uncovers a subtle signature in the RSNs of non-clinical adolescents who experienced task-induced ASEs.