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Reward motivation in individuals with high levels of negative schizotypal traits (NS) has been found to be lower than that in their counterparts. But it is unclear that whether their reward motivation adaptively changes with external effort-reward ratio, and what resting-state functional connectivity (rsFC) is associated with this change. Thirty-five individuals with high levels of NS and 44 individuals with low levels of NS were recruited. A 3T resting-state functional brain scan and a novel reward motivation adaptation behavioural task were administrated in all participants. The behavioural task was manipulated with three conditions (effort > reward condition vs. effort < reward condition vs. effort = reward condition). Under each condition were rated 'wanting' and 'liking' for rewards. The seed-based voxel-wise rsFC analysis was conducted to explore the rsFCs associated with the 'wanting' and 'liking' ratings in individuals with high levels of NS. 'Wanting' and 'liking' ratings of individuals with high levels of NS significantly declined in the effort > reward condition but did not rebound as high as their counterparts in the effort < reward condition. The rsFCs in NS group associated with these ratings were altered. The altered rsFCs in NS group involved regions in the prefrontal lobe, dopaminergic brain regions (ventral tegmental area, substantia nigra), hippocampus, thalamus and cerebellum. Individuals with high levels of NS manifested their reward motivation adaptation impairment as a failure of adjustment adaptively during effort-reward imbalance condition and altered rsFCs in prefrontal, dopaminergic and other brain regions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Schizotypy represents an index of psychosis-proneness in the general population, often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy., Methods: We addressed this question using data from a total of 1182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical gray matter volume and cortical thickness were determined., Results: A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of morphological changes directly associated with increasing levels of schizotypy or increasing levels of childhood trauma exposure., Conclusions: These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.

Psychiatric disorders show high co-morbidity, including co-morbid expressions of subclinical psychopathology across multiple disease spectra. Given the limitations of classical case-control designs in elucidating this overlap, new approaches are needed to identify biological underpinnings of spectra and their interaction. We assessed autistic-like traits (using the Autism Quotient, AQ) and schizotypy - as models of subclinical expressions of disease phenotypes and examined their association with volumes and regional cerebral blood flow (rCBF) of anterior, mid- and posterior hippocampus segments from  structural MRI scans in 318 and arterial spin labelling (ASL) in 346 nonclinical subjects, which overlapped with the structural imaging sample (N = 298). We demonstrate significant interactive effects of positive schizotypy and AQ social skills as well as of positive schizotypy and AQ imagination on hippocampal subfield volume variation. Moreover, we show that AQ attention switching modulated hippocampal head rCBF, while positive schizotypy by AQ attention to detail interactions modulated hippocampal tail rCBF. In addition, we show significant correlation of hippocampal volume and rCBF in both region-of-interest and voxel-wise analyses, which were robust after removal of variance related to schizotypy and autistic traits. These findings provide empirical evidence for both the modulation of hippocampal subfield structure and function through subclinical traits, and in particular how only the interaction of phenotype facets leads to significant reductions or variations in these parameters. This makes a case for considering the synergistic impact of different (subclinical) disease spectra on transdiagnostic biological parameters in psychiatry., (© 2023. The Author(s).)

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., Competing Interests: Declaration of Competing Interest PA has recived enterprise fuding from Opitibiotix Ltd UK, for work unrelated to the study reported here. RJ has been invited to expert boards by Lundbeck, Janssen, Rovi, and Otsuka. None of these links of interest are related to the present work. The other authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Inc.)

A growing body of research has placed the ventral striatum at the center of a network of cerebral regions involved in anticipating rewards in healthy controls. However, little is known about the functional connectivity of the ventral striatum associated with reward anticipation in healthy controls. In addition, few studies have investigated reward anticipation in healthy humans with different levels of schizotypy. Here, we investigated reward anticipation in eighty-four healthy individuals (44 females) recruited based on their schizotypy scores. Participants performed a variant of the Monetary Incentive Delay Task while undergoing event-related fMRI.Participants showed the expected decrease in response times for highly rewarded trials compared to non-rewarded trials. Whole-brain activation analyses replicated previous results, including activity in the ventral and dorsal striatum. Whole-brain psycho-physiological interaction analyses of the left and right ventral striatum revealed increased connectivity during reward anticipation with widespread regions in frontal, parietal and occipital cortex as well as the cerebellum and midbrain. Finally, we found no association between schizotypal personality severity and neural activity and cortico-striatal functional connectivity. In line with the motivational, attentional, and motor functions of rewards, our data reveal multifaceted cortico-striatal networks taking part in reward anticipation in healthy individuals. The ventral striatum is connected to regions of the salience, attentional, motor and visual networks during reward anticipation and thereby in a position to orchestrate optimal goal-directed behavior., (© 2023. The Author(s).)

Background: Mental time travel (MTT) is the ability to re-experience past events (autobiographic memory, AM) and pre-experience possible future events (episodic future thinking, EFT) through mental simulation. Empirical findings suggest that individuals with high level of schizotypy exhibit MTT impairment. However, the neural correlates of this impairment remain unclear., Method: Thirty-eight individuals with high level of schizotypy and 35 low level of schizotypy were recruited to complete an MTT imaging paradigm. Participants were required to recall past events (AM condition), imagine possible future events (EFT condition) related to cue words, or generate exemplars related to category words (control condition) while undergoing functional Magnetic Resonance Imaging (fMRI)., Results: AM showed greater activation in precuneus, bilateral posterior cingulate cortex, thalamus, and middle frontal gyrus than EFT. Individuals with high level of schizotypy exhibited reduced activation in the left anterior cingulate cortex during AM (vs. Control) and in the medial frontal gyrus during EFT (vs. Control) compared to individuals with low level of schizotypy. Although psychophysiological interaction analyses did not show any significant group difference, individuals with high level of schizotypy exhibited functional connectivity between left anterior cingulate cortex (seed) and right thalamus, between medial frontal gyrus (seed) and left cerebellum during MTT, whereas individuals with low level of schizotypy did not exhibit these functional connectivities., Conclusion: These findings suggest that decreased brain activations may underlie MTT deficits in individuals with high level of schizotypy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We analyzed the relationships between morphometric characteristics of brain gray matter and schizotypy. Mentally healthy subjects (n=164, age 18-35 years) completed Russian version of SPQ-74 test and underwent high-field 3T MRI. Cortical thickness in the right frontal pole (determined with FreeSurfer 6.0.0) positively correlated with negative schizotypy factor. The revealed features can reflect the protective mechanisms (resilience) against the development of mental disorders and also can be a result of individual ontogenesis trajectories manifested in deceleration of the decrease of the cortex thickness during first 3 decades of life., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

Both psychotic illness and subclinical psychosis-like experiences (PLEs) have been associated with cortico-striatal dysfunction. This work has largely relied on a discrete parcellation of the striatum into distinct functional areas, but recent evidence suggests that the striatum comprises multiple overlapping and smoothly varying gradients (i.e., modes) of functional organization. Here, we investigated two of these functional connectivity modes, previously associated with variations in the topographic patterning of cortico-striatal connectivity (first-order gradient), and dopaminergic innervation of the striatum (second-order gradient), and assessed continuities in striatal function from subclinical to clinical domains. We applied connectopic mapping to resting-state fMRI data to obtain the first-order and second-order striatal connectivity modes in two distinct samples: (1) 56 antipsychotic-free patients (26 females) with first-episode psychosis (FEP) and 27 healthy controls (17 females); and (2) a community-based cohort of 377 healthy individuals (213 females) comprehensively assessed for subclinical PLEs and schizotypy. The first-order "cortico-striatal" and second-order "dopaminergic" connectivity gradients were significantly different in FEP patients compared to controls bilaterally. In the independent sample of healthy individuals, variations in the left first-order "cortico-striatal" connectivity gradient were associated with inter-individual differences in a factor capturing general schizotypy and PLE severity. The presumed cortico-striatal connectivity gradient was implicated in both subclinical and clinical cohorts, suggesting that variations in its organization may represent a neurobiological trait marker across the psychosis continuum. Disruption of the presumed dopaminergic gradient was only noticeable in patients, suggesting that neurotransmitter dysfunction may be more apparent to clinical illness., (© 2023. The Author(s).)

Schizophrenia, a severe psychiatric disorder, is associated with abnormal brain activation during theory of mind (ToM) processing. Researchers recently suggested that there is a continuum running from subclinical schizotypal personality traits to fully expressed schizophrenia symptoms. Nevertheless, it remains unclear whether schizotypal personality traits in a nonclinical population are associated with atypical brain activation during ToM tasks. Our aim was to investigate correlations between fMRI brain activation during affective ToM (ToMA) and cognitive ToM (ToMC) tasks and scores on the Schizotypal Personality Questionnaire (SPQ) and the Basic Empathy Scale in 39 healthy individuals. The total SPQ score positively correlated with brain activation during ToMA processing in clusters extending from the left medial temporal gyrus (MTG), lingual gyrus and fusiform gyrus to the parahippocampal gyrus (Brodmann area: 19). During ToMA processing, the right inferior occipital gyrus, right MTG, precuneus and posterior cingulate cortex negatively correlated with the emotional disconnection subscore and the total score of self-reported empathy. These posterior brain regions are known to be involved in memory and language, as well as in creative reasoning, in nonclinical individuals. Our findings highlight changes in brain processing associated with trait schizotypy in nonclinical individuals during ToMA but not ToMC processing., (© The Author(s) 2023. Published by Oxford University Press.)

Previous behavioural data indicate lower word-nonword recognition accuracy in association with a high level of positive schizotypy, psychopathy, or motor impulsivity traits, each with some unique contribution, in the general population. This study aimed to examine the neural underpinnings of these associations using functional magnetic resonance imaging (fMRI) in a volunteer sample. Twenty-two healthy English-speaking adults completed self-report measures of schizotypy (Oxford-Liverpool Inventory of Feelings and Experiences [O-LIFE]), psychopathy (Triarchic Psychopathy Measure [TriPM]), and impulsivity (Barratt Impulsiveness Scale [BIS-11]) and underwent whole-brain fMRI while performing a lexical decision task (LDT) featuring high and low-frequency words, real nonwords, and pseudohomophones. Higher positive schizotypy (Unusual Experiences) was associated with lower cerebellum activity during identification of low-frequency words (over real nonwords). Higher Boldness (fearless dominance) and Meanness (callous aggression) facets of psychopathy were associated with lower striatal and posterior cingulate activity when identifying nonwords over words. Higher Motor Impulsivity was associated with lower activity in the fusiform (bilaterally), inferior frontal (right-sided), and temporal gyri (bilaterally) across all stimuli-types over resting baseline. Positive schizotypy, psychopathy, and impulsivity traits influence word-nonword recognition through distinct neurocognitive mechanisms. Positive schizotypy and psychopathy appear to influence LDT performance through brain areas that play only a supportive (cerebellum) or indirect role in reading-related skills. The negative association between Motor Impulsivity and activations typically found for phonological processing and automatic word identification indicates a reduced bilateral integration of the meaning and sound of mental word representations, and inability to select the appropriate outputs, in impulsive individuals., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Schizotypal personality disorder (SPD) resembles schizophrenia, but with attenuated brain abnormalities and the absence of psychosis. The thalamus is integral for processing and transmitting information across cortical regions and widely implicated in the neurobiology of schizophrenia. Comparing thalamic connectivity in SPD and schizophrenia could reveal an intermediate schizophrenia-spectrum phenotype to elucidate neurobiological risk and protective factors in psychosis. We used rsfMRI to investigate functional connectivity between the mediodorsal nucleus (MDN) and pulvinar, and their connectivity with frontal and temporal cortical regions, respectively in 43 healthy controls (HCs), and individuals in the schizophrenia-spectrum including 45 psychotropic drug-free individuals with SPD, and 20 individuals with schizophrenia-related disorders [(schizophrenia (n = 10), schizoaffective disorder (n = 8), schizophreniform disorder (n = 1) and psychosis NOS (n = 1)]. Individuals with SPD had greater functional connectivity between the MDN and pulvinar compared to individuals with schizophrenia. Thalamo-frontal (i.e., between the MDN and rostral middle frontal cortex) connectivity was comparable in SPD and HCs; in SPD greater connectivity was associated with less symptom severity. Individuals with schizophrenia had less thalamo-frontal connectivity and thalamo-temporal (i.e., pulvinar to the transverse temporal cortex) connectivity compared with HCs. Thalamo-frontal functional connectivity may be comparable in SPD and HCs, but abnormal in schizophrenia, and that this may be protective against psychosis in SPD., (Published by Elsevier B.V.)

Schizotypy is a latent cluster of personality traits that denote a vulnerability for schizophrenia or a type of spectrum disorder. The aim of the study is to investigate parametric effective brain connectivity features for classifying high versus low schizotypy (LS) status. Electroencephalography (EEG) signals are recorded from 13 high schizotypy (HS) and 11 LS participants during an emotional auditory odd-ball task. The brain connectivity signals for machine learning are taken after the settlement of event-related potentials. A multivariate autoregressive (MVAR)-based connectivity measure is estimated from the EEG signals using the directed transfer functions (DTFs) method. The values of DTF power in five standard frequency bands are used as features. The support vector machines (SVMs) revealed significant differences between HS and LS. The accuracy, specificity, and sensitivity of the results using SVM are as high as 89.21%, 90.3%, and 88.2%, respectively. Our results demonstrate that the effective brain connectivity in prefrontal/parietal and prefrontal/frontal brain regions considerably changes according to schizotypal status. These findings prove that the brain connectivity indices offer valuable biomarkers for detecting schizotypal personality. Further monitoring of the changes in DTF following the diagnosis of schizotypy may lead to the early identification of schizophrenia and other spectrum disorders.

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, p FDR  = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, p spin  = 0.024), but not BD (r = 0.166, p spin  = 0.205) or MDD (r = -0.274, p spin  = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, p spin  = 0.006), BD (rho = -0.672, p spin  = 0.009), and MDD (rho = -0.692, p spin  = 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., (© 2021. The Author(s).)

Background: Childhood trauma confers risk for psychosis and is associated with increased 'schizotypy' (a multi-dimensional construct reflecting risk for psychosis in the general population). Structural brain alterations are associated with both childhood trauma and schizotypy, but the potential role of trauma exposure in moderating associations between schizotypy and brain morphology has yet to be determined., Methods: Participants were 160 healthy individuals (mean age: 40.08 years, SD = 13.64, range 18-64; 52.5% female). Childhood trauma exposure was assessed using the Childhood Adversity Questionnaire, and schizotypy was assessed using the Schizotypal Personality Questionnaire. Univariate voxel-based morphometry and multivariate analyses of grey matter volume covariation (GMC; derived from independent component analysis) were performed to determine the main effects of schizotypy, trauma exposure and their interaction on these indices of grey matter volume. Moderation analyses were performed following significant interaction., Results: Levels of schizotypy, in particular the Cognitive-Perceptual and Interpersonal dimensions, were negatively associated with GMC in the striatum, the hippocampus/parahippocampal gyrus, thalamus and insulae. Trauma exposure was negatively associated with GMC of the middle frontal gyrus and parietal lobule, while negatively associated with GMC in the cerebellum. Levels of schizotypy (total scores, and the cognitive-perceptual dimension) were negatively associated with striatal GMC in individuals not exposed to trauma, but not in those exposed to trauma., Conclusions: Schizotypy and childhood trauma were independently associated with changes of grey matter in brain regions critical for cognition and social cognition. In individuals not exposed to trauma, increased schizotypy was associated with decreased striatal and limbic grey matter., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Schizotypy and psychotic-like experiences (PLE) form part of the wider psychosis continuum and may have brain structural correlates in nonclinical cohorts. This study aimed to compare the effects of differential schizotypy dimensions, PLE, and their interaction on hippocampal subfields and amygdala volumes in the absence of clinical psychopathology. In a cohort of 367 psychiatrically healthy individuals, we assessed schizotypal traits using the Oxford-Liverpool Inventory of Life Experiences (O-LIFE) and PLE using the short form of the Prodromal Questionnaire (PQ-16). Based on high-resolution structural MRI scans, we used automated segmentation to estimate volumes of limbic structures. Sex and total intracranial volume (Step 1), PLE and schizotypy dimensions (Step 2), and their interaction terms (Step 3) were entered as regressors for bilateral amygdala and hippocampal subfield volumes in hierarchical multiple linear regression models. Positive schizotypy, but not PLE, was negatively associated with left amygdala and subiculum volumes. O-LIFE Impulsive Nonconformity, as well as the two-way interaction between positive schizotypy and PLE, were associated with larger left subiculum volumes. None of the estimators for right hemispheric hippocampal subfield volumes survived correction for multiple comparisons. Our findings support differential associations of hippocampus subfield volumes with trait dimensions rather than PLE, and support overlap and interactions between psychometric positive schizotypy and PLE. In a healthy cohort without current psychosis risk syndromes, the positive association between PLE and hippocampal subfield volume occurred at a high expression of positive schizotypy. Further studies combining stable, transient, and genetic parameters are required., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Schizotypy refers to a multidimensional construct that spans a range of cognitive, behavioral, and personality features, representing liability to psychosis on a continuum between health and illness. Schizotypy has been associated with functional and structural brain alterations as potential intermediate phenotypes on the developmental path to psychosis. We scanned the literature between February 2019 and August 1, 2020 using PubMed, Medline, APA PsycINFO, and ProQuest. We identified eligible articles conducted on participants assessed with psychometric schizotypy across the health-illness spectrum and reporting a direct statistic between schizotypy and a structural, task-related, or functional magnetic resonance imaging brain measure. Articles not peer-reviewed and not written in English were excluded. We systematically reviewed 84 studies that determined the changes in gray matter, brain activation, and connectivity associated with schizotypy in both healthy and clinical cohorts. Morphological and functional changes in the default and the frontoparietal networks, specifically frontal and temporal cortices, were most frequently associated with schizotypy. Yet, we were unable to identify consistent patterns of morphological or functional brain aberration associated with schizotypy, due to methodological differences between studies in the conceptualization and measurement of schizotypy. Efforts toward greater methodological concordance in future neuroimaging research of schizotypy are needed to improve the identification of brain-based endophenotypes for schizophrenia. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of the Research: Cortico-striatal functional connectivity has been implicated in the neuropathology of schizophrenia. However, the longitudinal relationship between the cortico-striatal connectivity and schizotypy remains unknown. We examined the resting-state fMRI connectivity in 27 individuals with a high level of schizotypy and 20 individuals with a low level of schizotypy at baseline and 18 months later. Correlations between changes in cortico-striatal connectivity and changes in schizotypy scores over time were examined., Principal Results: We found both increased and decreased cortico-striatal connectivity in individuals with a high level of schizotypy at baseline. Over time, these individuals showed improvement in both the negative and positive schizotypal domains. Changes in striatal-insula connectivity were positively correlated with changes in positive schizotypy from baseline to follow-up., Major Conclusions: Our results suggested impaired cortico-striatal connectivity in individuals with a high level of schizotypy. The dysconnectivity mainly involves the dorsal striatum. The connectivity between the dorsal striatum and the insula may be a putative marker for temporal changes in positive schizotypy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Altered hippocampal functioning is proposed to play a critical role in the development of schizophrenia-spectrum disorders. Previous resting state functional Magnetic Resonance Imaging (rs-fMRI) studies report disrupted hippocampal connectivity in patients with psychosis and in individuals with clinical high risk, yet hippocampal connectivity has not been investigated in people with high schizotypy traits. Here we used rs-fMRI to examine hippocampal connectivity in healthy people with low (LS, n = 23) and high levels (HS, n = 22) of schizotypal traits assessed using the Schizotypy Personality Questionnaire. Using a bilateral hippocampal seed region, we examined resting state functional connectivity (RSFC) between hippocampus and striatal, thalamic and prefrontal cortex regions of interest. Compared to LS, HS participants showed lower RSFC between hippocampus and striatum and between hippocampus and thalamus. Whilst the group effect of reduced hippocampal RSFC in striatal and thalamic regions was driven by total schizotypy scores, positive schizotypy subfactor scores were significantly positively correlated with hippocampus-caudate/thalamus RSFC. Group differences in RSFC were not observed between hippocampus and prefrontal cortex. These results demonstrate that subclinical schizotypal traits are associated with altered hippocampal connectivity in striatal and thalamic regions and provide further support that hippocampal dysconnectivity confers risk for schizophrenia spectrum disorders., (Copyright © 2020. Published by Elsevier B.V.)

Numerous studies have implicated involvement of the hippocampus in the etiology and expression of schizophrenia-spectrum psychopathology, and reduced hippocampal volume is one of the most robust brain abnormalities reported in schizophrenia. Recent studies indicate that early stages of schizophrenia are specifically characterized by reductions in anterior hippocampal volume; however, studies have not examined hippocampal volume reductions in subclinical schizotypy. The present study was the first to examine the associations of positive, negative, and disorganized schizotypy dimensions with hippocampal subfield volumes in a large sample (n = 195) of nonclinically ascertained young adults, phenotyped using the Multidimensional Schizotypy Scale (MSS). Hippocampal subfields were analyzed from high-resolution 3 Tesla structural magnetic resonance imaging scans testing anatomical models, including anterior vs posterior regions and the cornu ammonis (CA), dentate gyrus (DG), and subiculum subfields separately for the left and right hemispheres. We demonstrate differential spatial effects across anterior vs posterior hippocampus segments across different dimensions of the schizotypy risk phenotype. The interaction of negative and disorganized schizotypy robustly predicted left hemisphere volumetric reductions for the anterior and total hippocampus, and anterior CA and DG, and the largest reductions were seen in participants high in negative and disorganized schizotypy. These findings extend previous early psychosis studies and together with behavioral studies of hippocampal-related memory impairments provide the basis for a dimensional neurobiological hippocampal model of schizophrenia risk. Subtle hippocampal subfield volume reductions may be prevalent prior to the onset of detectable prodromal clinical symptoms of psychosis and play a role in the etiology and development of such conditions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Schizotypal Personality Disorder (SPD) is a cluster A personality disorder affecting 1.0% of the general population, characterised by disturbances in cognition and reality testing dimensions, affected regulation, and interpersonal function. SPD shares similar but attenuated phenomenological, genetic, and neurobiological abnormalities with Schizophrenia (SCZ) and is described as part of schizophrenia spectrum disorders., Objective: The aim of this work was to identify major neural correlates of SPD., Methods: This is a systematic review conducted according to PRISMA statement. The protocol was prospectively registered in PROSPERO - International prospective register of systematic reviews. The review was performed to summarise the most comprehensive and updated evidence on functional neuroimaging and neurophysiology findings obtained through different techniques (DW- MRI, DTI, PET, SPECT, fMRI, MRS, EEG) in individuals with SPD., Results: Of the 52 studies included in this review, 9 were on DW-MRI and DTI, 11 were on PET and SPECT, 11 were on fMRI and MRS, and 21 were on EEG. It was complex to synthesise all the functional abnormalities found in a single, unified, pathogenetic pathway, but a common theme emerged: the dysfunction of brain circuits including striatal, frontal, temporal, limbic regions (and their networks) together with a dysregulation along the dopaminergic pathways., Conclusion: Brain abnormalities in SPD are similar, but less marked, than those found in SCZ. Furthermore, different patterns of functional abnormalities in SPD and SCZ have been found, confirming the previous literature on the 'presence' of possible compensatory factors, protecting individuals with SPD from frank psychosis and providing diagnostic specificity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In this study, we examined differences in resting-state functional connectivity between sub-regions of the Default Mode Network (DMN) and whole brain voxels in 22 individuals with high schizo-obsessive traits (SOT), 30 with high schizotypal traits (SCT) alone, 20 with high obsessive-compulsive traits (OCT) alone and 30 with low trait scores (LT). We found that the SOT group showed the most reduced functional connectivity within the DMN compared with the other groups. The SOT group also showed increased connectivity between the DMN and the Salience Network, and between the DMN and the Auditory Network compared with the LT group. The SCT group exhibited increased connectivity between the DMN and the Salience Network, and between the DMN and the Executive Control Network (ECN) compared with the LT group. The OCT group exhibited decreased connectivity within the DMN, between the DMN and the Salience Network, and between the DMN and the ECN compared with the LT group. These findings highlight different changes in DMN-related functional connectivity associated with high SOT, SCT and OCT traits and may provide insight into the dysfunctional brain networks in the early stage of schizophrenia spectrum disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, we applied brain grey matter volume and structural covariance methods on T1 weighted images to delineate potential structural brain changes in individuals with high schizotypy, who were defined as healthy individuals scoring in the top tenth percentile of the Schizotypal Personality Questionnaire (SPQ). Eighty-seven college students with high schizotypy and 122 controls were recruited in China. Differences in grey matter volume and volume covariance between the two groups, and correlations of grey matter volume with SPQ scores in the high schizotypy group were examined. We found that individuals with high schizotypy had decreased grey matter volume at the left medial superior frontal gyrus (medsFG) extending towards the superior frontal gyrus, decreased structural covariance within the right medsFG, between the right superior frontal gyrus (sFG), the right superior temporal gyrus and the right anterior insula; and increased structural covariance between the caudate and the right inferior temporal gyrus. Correlation analysis revealed that grey matter volume of the left middle temporal pole and the right sFG correlated positively with the SPQ total scores, volume of the bilateral cerebellum 9 sub-region correlated negatively with the SPQ cognitive-perceptual sub-scale scores, volume of the bilateral striatum correlated positively with the SPQ interpersonal sub-scale scores, and volume of the bilateral superior temporal pole correlated positively with the SPQ disorganization sub-scale scores in the high schizotypy group. These results highlight important grey matter structural changes in the medsFG in individuals with high schizotypy., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale: Previous research has suggested that schizotypal personality disorder (SPD), a condition that shares clinical and cognitive features with schizophrenia, may be associated with elevated striatal dopamine functioning; however, there are no published studies of dopamine release within subregions of the striatum in SPD., Objectives: To characterize dopamine release capacity in striatal subregions and its relation to clinical and cognitive features in SPD., Methods: We used positron emission tomography with [ 11 C]raclopride and an amphetamine challenge to measure dopamine D2-receptor availability (binding potential, BP ND ), and its percent change post-amphetamine (∆BP ND ) to index amphetamine-induced dopamine release, in subregions of the striatum in 16 SPD and 16 healthy control participants. SPD participants were evaluated with measures of schizotypal symptom severity and working memory., Results: There were no significant group differences in BP ND or ∆BP ND in any striatal subregion or whole striatum. Among SPD participants, cognitive-perceptual symptoms were associated at trend level with ∆BP ND in the ventral striatum, and disorganized symptoms were significantly negatively related to ∆BP ND in several striatal subregions., Conclusions: In contrast to previous findings, SPD was not associated with elevated striatal dopamine release. However, in SPD, there was a moderate positive association between ventral striatal dopamine release and severity of cognitive-perceptual symptoms, and negative associations between striatal dopamine release and severity of disorganized symptoms. Future larger scale investigations that allow for the separate examination of subgroups of participants based on clinical presentation will be valuable in further elucidating striatal DA functioning in SPD.

Schizotypy is a multidimensional construct of subclinical schizophrenia-like behavioural traits and cognition. The recently developed multidimensional schizotypy scale (MSS) provides an improved psychometric assessment of the three main dimensions (positive, negative, and disorganised). We tested the hypothesis that the three dimensions are related to brain structural variation in the precuneus and fronto-thalamo-striatal system in a new non-clinical healthy cohort to support a dimensional model of the psychosis spectrum. We analysed data from 104 subjects with Multidimensional Schizotypy Scale (MSS) phenotyping and 3 Tesla magnetic resonance images using voxel-based morphometry (VBM) applying CAT12 software, and diffusion-tensor imaging (DTI) with TBSS in FSL to test for correlations with MSS scores. MSS subscales and total score were negatively associated with GMV in brain areas including the medial prefrontal cortex, anterior cingulate cortex, and lateral prefrontal and orbital cortex. MSS schizotypy was associated with white matter integrity in anterior thalamic radiation, uncinate fasciculus, and superior longitudinal fasciculus. Our findings provide first direct evidence for an association of schizotypy (as a psychosis risk phenotype) and the fronto-thalamo-striatal system, in both grey and white matter with regionally diverging effects across single dimensions. This provides new evidence arguing for the fronto-striatal system (rather than precuneus) in schizotypy., Competing Interests: Declaration of competing Interest All authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Schizotypal traits are considered as inheritable traits and the endophenotype for schizophrenia. A common variant in the NOTCH4 gene, rs204993, has been linked with schizophrenia, but the neural underpinnings are largely unknown., Methods: In present study, we compared the differences of brain functions between different genotypes of rs204993 and its relationship with schizotypal traits among 402 Chinese Han healthy volunteers. The brain function was evaluated with functional connectivity strength (FCS) using the resting-state functional magnetic resonance image(rs-fMRI). The schizotypal traits were measured by the schizotypal personality questionnaire (SPQ)., Results: Our results showed that carriers with the AA genotype showed reduced FCS in the left occipital cortex when compared with carriers with the AG and GG genotypes, and the carriers with the AG genotype showed reduced FCS in the left occipital cortex when compared with carriers with the GG genotype. The FCS values in the left occipital lobe were negatively associated with the SPQ scores and its subscale scores within the carriers with the GG genotype, but not within the carriers with AA or AG genotype., Conclusion: Our results suggested that the common variant in the NOTCH4 gene, rs204993, modulates the function of the occipital cortex, which may contribute to schizotypal traits. These findings provide insight for genetic effects on schizotypal traits and its potential neural substrate.

Background: Previous models suggest biological and behavioral continua among healthy individuals (HC), at-risk condition, and full-blown schizophrenia (SCZ). Part of these continua may be captured by schizotypy, which shares subclinical traits and biological phenotypes with SCZ, including thalamic structural abnormalities. In this regard, previous findings have suggested that multivariate volumetric patterns of individual thalamic nuclei discriminate HC from SCZ. These results were obtained using machine learning, which allows case-control classification at the single-subject level. However, machine learning accuracy is usually unsatisfactory possibly due to phenotype heterogeneity. Indeed, a source of misclassification may be related to thalamic structural characteristics of those HC with high schizotypy, which may resemble structural abnormalities of SCZ. We hypothesized that thalamic structural heterogeneity is related to schizotypy, such that high schizotypal burden would implicate misclassification of those HC whose thalamic patterns resemble SCZ abnormalities., Methods: Following a previous report, we used Random Forests to predict diagnosis in a case-control sample (SCZ = 131, HC = 255) based on thalamic nuclei gray matter volumes estimates. Then, we investigated whether the likelihood to be classified as SCZ (π-SCZ) was associated with schizotypy in 174 HC, evaluated with the Schizotypal Personality Questionnaire., Results: Prediction accuracy was 72.5%. Misclassified HC had higher positive schizotypy scores, which were correlated with π-SCZ. Results were specific to thalamic rather than whole-brain structural features., Conclusions: These findings strengthen the relevance of thalamic structural abnormalities to SCZ and suggest that multivariate thalamic patterns are correlates of the continuum between schizotypy in HC and the full-blown disease.

Individuals with autism spectrum disorder and individuals with schizophrenia have impaired social and communication skills. They also have altered auditory perception. This study investigated autistic traits and schizotypy in a non-clinical population as well as the excitation-inhibition (EI) balance in different brain regions and their auditory multistable perception. Thirty-four healthy participants were assessed by the Autism-Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ). The EI balance was evaluated by measuring the resting-state concentrations of glutamate-glutamine (Glx) and ϒ-aminobutyric acid (GABA) in vivo by using magnetic resonance spectroscopy. To observe the correlation between their traits and perception, we conducted an auditory streaming task and a verbal transformation task, in which participants reported spontaneous perceptual switching while listening to a sound sequence. Their AQ and SPQ scores were positively correlated with the Glx/GABA ratio in the auditory cortex but not in the frontal areas. These scores were negatively correlated with the number of perceptual switches in the verbal transformation task but not in the auditory streaming task. Our results suggest that the EI balance in the auditory cortex and the perceptual formation of speech are involved in autistic traits and schizotypy.

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., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several lines of evidence identify aberrant excitatory-inhibitory neural processes across autism and schizophrenia spectrum disorders, particularly within the psychosocial domain. Such neural processes include increased excitatory glutamate and reduced inhibitory GABA concentrations, which may affect auditory pre-attentive processing as indexed by the mismatch negativity (MMN); thus, an excitation-inhibition imbalance might lead to aberrant MMN, which might in turn drive the relationship between the MMN and psychosocial difficulties. This research has the potential to enhance the neurochemical understanding of the relationship between electrophysiology (MMN) and behavioural/clinical measures (psychosocial difficulties). Thirty-eight adults (18 male, 18-40 years) completed the Schizotypal Personality Questionnaire (SPQ) and Autism-Spectrum Quotient (AQ). Glutamate and GABA concentrations in bilateral superior temporal cortex (STC) were quantified using proton magnetic resonance spectroscopy (1H-MRS) while auditory MMN to a duration deviant was measured with magnetoencephalography. Spearman correlations probed the relationships between STC glutamate/GABA ratios, MMN amplitude and latency, and AQ and SPQ dimensions. Mediation effects of glutamate/GABA ratios on the relationship between MMN and AQ-SPQ dimensions were probed using causal mediation analysis. Only SPQ-interpersonal and AQ-communication were significantly correlated with right hemisphere glutamate/GABA ratios and MMN latency (ps < 0.05), which were themselves correlated (p = .035). Two mediation models were investigated, with right MMN latency as predictor and SPQ-interpersonal and AQ-communication as outcome variables. Right STC glutamate/GABA ratios significantly mediated the relationship between MMN latency and SPQ-interpersonal scores, but only partially mediated the relationship between MMN latency and AQ-communication scores. These findings support the growing body of literature pointing toward an excitation-inhibition imbalance that is central to psychosocial functioning across multi-dimensional spectrum disorders, such as autism and schizophrenia, and provides neurochemical indicators of the processes that underlie psychosocial dysfunction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Schizotypal disorder is characterized by odd behavior and attenuated forms of schizophrenic features without the manifestation of overt and sustained psychoses. Past studies suggest that schizotypal disorder shares biological and psychological commonalties with schizophrenia. Structural magnetic resonance imaging (MRI) studies have demonstrated both common and distinct regional gray matter changes between schizophrenia and schizotypal disorder. However, no study has compared cortical thickness, which is thought to be a specific indicator of cortical atrophy, between schizophrenia and schizotypal disorder. The subjects consisted of 102 schizophrenia and 46 schizotypal disorder patients who met the International Classification of Diseases, 10th edition criteria and 79 gender- and age-matched healthy controls. Each participant underwent a T1-weighted 3-D MRI scan using a 1.5-Tesla scanner. Cortical thickness was estimated using FreeSurfer. Consistent with previous studies, schizophrenia patients exhibited wide-spread cortical thinning predominantly in the frontal and temporal regions as compared with healthy subjects. Patients with schizotypal disorder had a significantly reduced cortical thickness in the left fusiform and parahippocampal gyri, right medial superior frontal gyrus, right inferior frontal gyrus, and right medial orbitofrontal cortex as compared with healthy controls. Schizophrenia patients had thinner cortices in the left precentral and paracentral gyri than those with schizotypal disorder. Common cortical thinning patterns observed in schizophrenia and schizotypal disorder patients may be associated with vulnerability to psychosis. Our results also suggest that distinct cortical changes in schizophrenia and schizotypal disorder may be associated with the differences in the manifestation of clinical symptoms among these disorders., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Continued human and animal research has strengthened evidence for aberrant excitatory-inhibitory neural processes underlying autism and schizophrenia spectrum disorder psychopathology, particularly psychosocial functioning, in clinical and nonclinical populations. We investigated the extent to which autistic traits and schizotypal dimensions were modulated by the interactive relationship between excitatory glutamate and inhibitory GABA neurotransmitter concentrations in the social processing area of the superior temporal cortex using proton magnetic resonance spectroscopy. In total, 38 non-clinical participants (20 females; age range = 18-35 years, mean (standard deviation) = 23.22 (5.52)) completed the autism spectrum quotient and schizotypal personality questionnaire, and underwent proton magnetic resonance spectroscopy to quantify glutamate and GABA concentrations in the right and left superior temporal cortex. Regression analyses revealed that glutamate and GABA interactively modulated autistic social skills and schizotypal interpersonal features ( p corr < 0.05), such that those with high right superior temporal cortex glutamate but low GABA concentrations exhibited poorer social and interpersonal skills. These findings evidence an excitation-inhibition imbalance that is specific to psychosocial features across the autism and schizophrenia spectra.

Social cognition refers to the mental operations governing social interactions. Recent research has highlighted the importance of social cognition in determining functional outcome in patients with schizophrenia and in psychosis risk populations. The aim of this review is to investigate the neural correlates of social cognition in different psychosis risk populations, potentially representing different levels of risk i.e. high schizotypy (SR), familial risk (FR) and clinical high risk (CHR). PsychINFO, Web of Science and PubMed were systematically searched, and 39 papers were included in the final review. Results in FR samples were highly inconclusive. In SR samples, findings showed a tendency towards increased task related activity in frontal cortex regions. The most consistent results come from CHR samples, where findings suggest increased task related activity in frontal and cingulate cortices. Interestingly, all studies of CHR populations also report increased activity in temporal cortex and abnormal response to neutral stimuli during emotional processing tasks. These findings are discussed in relation to dopamine models of psychosis due to temporal cortex abnormality., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: Increased brain gyrification in diverse cortical regions has been reported in patients with schizophrenia, possibly reflecting deviations in early neurodevelopment. However, it remains unknown whether patients with schizotypal disorder exhibit similar changes., Methods: This magnetic resonance imaging study investigated brain gyrification in 46 patients with schizotypal disorder (29 male, 17 female), 101 patients with schizophrenia (55 male, 46 female), and 77 healthy controls (44 male, 33 female). T1-weighted magnetic resonance images were obtained for each participant. Using FreeSurfer software, the local gyrification index (LGI) of the entire cortex was compared across the groups., Results: Both schizophrenia and schizotypal disorder patients showed a significantly higher LGI in diverse cortical regions, including the bilateral prefrontal and left parietal cortices, as compared with controls, but its extent was broader in schizophrenia especially for the right prefrontal and left occipital regions. No significant correlations were found between the LGI and clinical variables (e.g., symptom severity, medication) for either of the patient groups., Conclusion: Increased LGI in the frontoparietal regions was common to both patient groups and might represent vulnerability to schizophrenia, while more diverse changes in schizophrenia patients might be associated with the manifestation of florid psychosis., (© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology.)

Despite considerable phenomentological differences between borderline personality disorder (BPD) and schizotypal personality disorder (SPD), research increasingly provides evidence that some BPD symptoms overlap with SPD symptoms (e.g., disturbed cognitions). We examined the cingulate, a brain region implicated in the pathophysiology of both disorders, to determine similarities/differences between the groups, and similarities/differences from healthy controls (HC's). 3T structural and diffusion tensor magnetic resonance imaging scans were acquired in BPD (n = 27), SPD (n = 32), HC's (n = 34). Results revealed that BPD patients exhibited significantly lower FA in posterior cingulate white matter compared to HC's (p = 0.04), but SPD patients did not., (Published by Elsevier B.V.)

Psychosis is linked to aberrant salience or to viewing neutral stimuli as self-relevant, suggesting a possible impairment in self-relevance processing. Psychosis is also associated with increased dopamine in the dorsal striatum, especially the anterior caudate (Kegeles et al., 2010). Critically, the anterior caudate is especially connected to (a) the cortical default mode network (DMN), centrally involved in self-relevance processing, and (b) to a lesser extent, the cortical frontoparietal network (FPN; Choi, Yeo, & Buckner, 2012). However, no previous study has directly examined striatal-cortical DMN connectivity in psychosis risk. In Study 1, we examined resting-state functional connectivity in psychosis risk (n = 18) and control (n = 19) groups between (a) striatal DMN and FPN subregions and (b) cortical DMN and FPN. The psychosis risk group exhibited decreased connectivity between the striatal subregions and the cortical DMN. In contrast, the psychosis risk group exhibited intact connectivity between the striatal subregions and the cortical FPN. Additionally, recent distress was also associated with decreased striatal-cortical DMN connectivity. In Study 2, to determine whether the decreased striatal-cortical DMN connectivity was specific to psychosis risk or was related to recent distress more generally, we examined the relationship between connectivity and distress in individuals diagnosed with nonpsychotic emotional distress disorders (N = 25). In contrast to Study 1, here we found that distress was associated with evidence of increased striatal-cortical DMN connectivity. Overall, the present results suggest that decreased striatal-cortical DMN connectivity is associated with psychosis risk and could contribute to aberrant salience.

The dopamine hypothesis of schizophrenia implies that alterations in the dopamine system cause functional abnormalities in the brain that may converge to aberrant salience attribution and eventually lead to psychosis. Indeed, widespread brain disconnectivity across the psychotic spectrum has been revealed by resting-state functional magnetic resonance imaging (rs-fMRI). However, the dopaminergic involvement in intrinsic functional connectivity (iFC) and its putative relationship to the development of psychotic spectrum disorders remains partly unclear-in particular at the low-end of the psychosis continuum. Therefore, we investigated dopamine-induced changes in striatal iFC and their modulation by psychometrically assessed schizotypy. Our randomized, double-blind placebo-controlled study design included 54 healthy, right-handed male participants. Each participant was assessed with the Schizotypal Personality Questionnaire (SPQ) and underwent 10 minutes of rs-fMRI scanning. Participants then received either a placebo or 200 mg of L-DOPA, a dopamine precursor. We analyzed iFC of 6 striatal seeds that are known to evoke modulation of dopamine-related networks. The main effect of L-DOPA was a significant functional decoupling from the right ventral caudate to both occipital fusiform gyri. This dopamine-induced decoupling emerged primarily in participants with low SPQ scores, while participants with high positive SPQ scores showed decoupling indifferently of the L-DOPA challenge. Taken together, these findings demonstrate that schizotypal traits may be the result of dopamine-induced striato-occipital decoupling., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This is a selective review of the work of Buchsbaum and colleagues. It revisits and pays tribute to four decades of publications employing positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) to examine the neurobiology of schizophrenia-spectrum disorders (including schizotypal personality disorder (SPD) and schizophrenia). Beginning with a landmark FDG-PET study in 1982 reporting hypofrontality in unmedicated schizophrenia patients, Buchsbaum and colleagues published high-impact work on regional glucose metabolic rate (GMR) abnormalities in the spectrum. Several key discoveries were made, including the delineation of schizophrenia-spectrum abnormalities in frontal and temporal lobe, cingulate, thalamus, and striatal regions using three-dimensional mapping with coregistered MRI and PET. These findings indicated that SPD patients have less marked frontal lobe and striatal dysfunction compared with schizophrenia patients, possibly mitigating frank psychosis. Additionally, these investigations were among the first to conduct early seed-based functional connectivity analyses with FDG-PET, showing aberrant cortical-subcortical circuitry and, in particular, revealing a thalamocortical circuitry abnormality in schizophrenia. Finally, pioneering work employing the first double-blind randomized antipsychotic (haloperidol) vs. placebo FDG-PET study design in schizophrenia indicated that GMR in the striatum, more than in any other region, was related to clinical response., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Impairment in facial emotion perception is an important domain of social cognition deficits in schizophrenia. Although impaired facial emotion perception has been found in individuals with negative schizotypy (NS), little is known about the corresponding change in brain functional connectivity., Methods: Sixty-four participants were classified into a high NS group (n = 34) and a low NS group (n = 30) based on their total scores on the Chapman scales for physical and social anhedonia. All participants undertook a facial emotion discrimination functional imaging task that consisted of four emotional valences (angry, fear, happy, and neutral). For univariate analysis, the signal change at the bilateral amygdala was compared for each emotional contrast using SPSS (P < .05). For the functional connectivity analysis, we calculated the beta-series functional connectivity of the bilateral amygdala with the medial prefrontal cortex (mPFC) and compared the group differences in SPM12 (P < .05, small volume family-wise error correction)., Results: No significant differences were found between the high and low NS groups in accuracy and reaction time in the facial emotion discrimination task. The high NS group showed reduced brain activations at the amygdala under fearful and neutral conditions. Reduced functional connectivity between the amygdala and the mPFC/dorsal anterior cingulate cortex under the happy and fearful conditions in the high NS group was also found., Conclusions: Our findings suggest that the individuals with high NS showed altered brain activity and functional connectivity at the amygdala during facial emotion processing and provide new evidence for understanding social cognition deficits in at-risk individuals.

Functional magnetic resonance imaging is capable of estimating functional activation and connectivity in the human brain, and lately there has been increased interest in the use of these functional modalities combined with machine learning for identification of psychiatric traits. While these methods bear great potential for early diagnosis and better understanding of disease processes, there are wide ranges of processing choices and pitfalls that may severely hamper interpretation and generalization performance unless carefully considered. In this perspective article, we aim to motivate the use of machine learning schizotypy research. To this end, we describe common data processing steps while commenting on best practices and procedures. First, we introduce the important role of schizotypy to motivate the importance of reliable classification, and summarize existing machine learning literature on schizotypy. Then, we describe procedures for extraction of features based on fMRI data, including statistical parametric mapping, parcellation, complex network analysis, and decomposition methods, as well as classification with a special focus on support vector classification and deep learning. We provide more detailed descriptions and software as supplementary material. Finally, we present current challenges in machine learning for classification of schizotypy and comment on future trends and perspectives.

Arterial spin labeling (ASL) provides absolute quantification of resting tissue cerebral blood flow (CBF) as an entirely noninvasive approach with good reproducibility. As a result of neurovascular coupling, ASL provides a useful marker of resting neuronal activity. Recent ASL studies in individuals at clinical high risk of psychosis (CHR) have reported increased resting hippocampal perfusion compared with healthy controls. Schizotypy refers to the presence of subclinical psychotic-like experiences in healthy individuals and represents a robust framework to study neurobiological mechanisms involved in the extended psychosis phenotype while avoiding potentially confounding effects of antipsychotic medications or disease comorbidity. Here we applied pseudo-continuous ASL to examine differences in resting CBF in 21 subjects with high positive schizotypy (HS) relative to 22 subjects with low positive schizotypy (LS), as determined by the Oxford and Liverpool Inventory of Feelings and Experiences. Based on preclinical evidence that hippocampal hyperactivity leads to increased activity in mesostriatal dopamine projections, CBF in hippocampus, midbrain, and striatum was assessed. Participants with HS showed higher CBF of the right hippocampus compared to those with LS (p = .031, family-wise error corrected). No differences were detected in the striatum or midbrain. The association between increased hippocampal CBF and HS supports the notion that hippocampal hyperactivity might be a central characteristic of the extended psychosis phenotype, while hyperactivity in subcortical dopamine pathways may only emerge at a higher intensity of psychotic experiences., (© 2018 Wiley Periodicals, Inc.)

Background: Cortical glutamatergic dysfunction is thought to be fundamental for psychosis development, and may lead to structural degeneration through excitotoxicity. Glutamate levels have been related to gray matter volume (GMV) alterations in people at ultra-high risk of psychosis, and we previously reported GMV changes in individuals with high schizotypy (HS), which refers to the expression of schizophrenia-like characteristics in healthy people. This study sought to examine whether GMV changes in HS subjects are related to glutamate levels., Methods: We selected 22 healthy subjects with HS and 23 healthy subjects with low schizotypy (LS) based on their rating on a self-report questionnaire for psychotic-like experiences. Glutamate levels were measured in the bilateral anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, and GMV was assessed using voxel-based morphometry., Results: Subjects with HS showed GMV decreases in the rolandic operculum/superior temporal gyrus (pFWE = 0.045). Significant increases in GMV were also detected in HS, in the precuneus (pFWE = 0.043), thereby replicating our previous finding in a separate cohort, as well as in the ACC (pFWE = 0.041). While the HS and LS groups did not differ in ACC glutamate levels, in HS subjects ACC glutamate was negatively correlated with ACC GMV (pFWE = 0.026). Such association was absent in LS., Conclusions: Our study shows that GMV findings in schizotypy are related to glutamate levels, supporting the hypothesis that glutamatergic function may lead to structural changes associated with the expression of psychotic-like experiences.

Abnormalities in temporal and frontal cortical volume, white matter tract integrity, and hemispheric asymmetry have been implicated in schizophrenia-spectrum disorders. Schizotypal personality disorder can provide insight into vulnerability and protective factors in these disorders without the confounds associated with chronic psychosis. However, multimodal imaging and asymmetry studies in SPD are sparse. Thirty-seven individuals with SPD and 29 healthy controls (HC) received clinical interviews and 3T magnetic resonance T1-weighted and diffusion tensor imaging scans. Mixed ANOVAs were performed on gray matter volumes of the lateral temporal regions involved in auditory and language processing and dorsolateral prefrontal cortex involved in executive functioning, as well as fractional anisotropy (FA) of prominent white matter tracts that connect frontal and temporal lobes. In the temporal lobe regions, there were no group differences in volume, but SPD had reduced right>left middle temporal gyrus volume asymmetry compared to HC and lacked the right>left asymmetry in the inferior temporal gyrus volume seen in HC. In the frontal regions, there were no differences between groups on volume or asymmetry. In the white matter tracts, SPD had reduced FA in the left sagittal stratum and superior longitudinal fasciculus, and increased right>left asymmetry in sagittal stratum FA compared to HC. In the SPD group, lower left superior longitudinal fasciculus FA was associated with greater severity of disorganization symptoms. Findings suggest that abnormities in structure and asymmetry of temporal regions and frontotemporal white matter tract integrity are implicated in SPD pathology., (Published by Elsevier B.V.)

Background: Hippocampal abnormalities have been largely reported in patients with schizophrenia and bipolar disorder, and are considered to be involved in the pathophysiology of the psychosis. The hippocampus consists of several subfields but it remains unclear their involvement in the early stages of psychosis., Aim: The aim of this study was to investigate volumetric alterations in hippocampal subfields in patients at the first-episode psychosis (FEP)., Methods: Magnetic resonance imaging (MRI) data were collected in 134 subjects (58 FEP patients; 76 healthy controls [HC]). A novel automated hippocampal segmentation algorithm was used to segment the hippocampal subfields, based on an atlas constructed from ultra-high resolution imaging on ex vivo hippocampal tissue. The general linear model was used to investigate volume differences between FEP patients and HC, with age, gender and total intracranial volume as covariates., Results: We found significantly lower volumes of bilateral CA1, CA4, and granule cell layer (GCL), and of left CA3, and left molecular layer (ML) in FEP patients compared to HC. Only the volumes of the left hippocampus and its subfields were significantly lower in FEP than HC at the False Discovery Rate (FDR) of 0.1. No correlation was found between hippocampal subfield volume and duration of illness, age of onset, duration of medication, and Positive and Negative Syndrome Scale (PANSS)., Conclusion: We report abnormally low volumes of left hippocampal subfields in patients with FEP, sustaining its role as a putative neural marker of psychosis onset.

Striatal abnormalities play a crucial role in the pathophysiology of schizophrenia. Growing evidence suggests an association between aberrant striatal activity during reward anticipation and symptom dimensions in schizophrenia. However, it is not clear whether this holds across the psychosis continuum. The aim of the present study was to investigate alterations of ventral striatal activation during reward anticipation and its relationship to symptom expression in persons with schizotypal personality traits (SPT) and first-episode psychosis. Twenty-six individuals with high SPT, 26 patients with non-affective first-episode psychosis (including 13 with brief psychotic disorder (FEP-BPD) and 13 with first-episode schizophrenia [FEP-SZ]) and 25 healthy controls underwent event-related functional magnetic resonance imaging while performing a variant of the Monetary Incentive Delay task. Ventral striatal activation was positively correlated with total symptom severity, in particular with levels of positive symptoms. This association was observed across the psychosis continuum and within each subgroup. Patients with FEP-SZ showed the strongest elevation of striatal activation during reward anticipation, although symptom levels did not differ between groups in the psychosis continuum. While our results provide evidence that variance in striatal activation is mainly explained by dimensional symptom expression, patients with schizophrenia show an additional dysregulation of striatal activation. Trans-diagnostic approaches are promising in order to disentangle dimensional and categorical neural mechanisms in the psychosis continuum., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

To study white matter changes in schizotypal personality disorder (SPD), we developed a new statistical analysis method based on supervoxels for diffusion tensor imaging. Twenty patients with SPD and eighteen healthy controls were recruited from a pool of 3000 first-year university undergraduates, and underwent MRI using a 3T scanner. Diffusion tensors were first normalized into ICBM-152 space followed by a supervoxel segmentation based on graph clustering to segment white matter tensors into diffusion homogeneous supervoxels. Fractional anisotropy (FA) values in supervoxels were compared between SPD and healthy controls using permutation test. Suprathreshold cluster size test was used to correct multiple comparison. At last, fibers with significant differences were extracted from supervoxel clusters with significance level P < 0.05. Results showed that FA values in genu of corpus callosum were significantly reduced (P = 0.012) in patients with SPD (FA = 0.565) compared with healthy controls (FA = 0.593). In summary, this study proposed a novel supervoxel segmentation method for diffusion tensor imaging using graph-based clustering, and extended permutation test and suprathreshold cluster size test to supervoxels for detection of white matter changes., (Copyright © 2017. Published by Elsevier Inc.)

Background: There are overlaps between autism and schizophrenia but these are particularly pronounced, especially in social domains, for higher functioning individuals with autism spectrum disorders (ASD) or schizotypal personality disorder (SPD). It is not known whether these overlapping social deficits result from shared or distinct brain mechanisms. We therefore compared social cognition in ASD and SPD using functional magnetic resonance imaging (fMRI)., Methods: Twenty-one individuals with SPD, 28 with ASD and 33 controls were compared with respect to clinical symptoms using the Positive and Negative Syndrome Scale; social cognition, using a social judgment task and Ekman 60 faces task; and brain activation using an fMRI task of social judgment., Results: The ASD and SPD groups showed few differences in symptoms or social cognition. However, fMRI showed that, compared to ASD, the SPD group showed significantly greater activation during social compared to gender judgments in the amygdala and 3 clusters: right posterior cerebellum, extending into fusiform and inferior temporal gyri; left posterior cerebellum; and left intraparietal sulcus extending through medial portions of the temporal gyri into the fusiform gyrus (all P < .05 family-wise error corrected). Control activations lay between the ASD and SPD groups., Conclusions: Although social cognitive deficits in ASD and SPD appear superficially similar they are the result of different brain mechanisms. These findings have implications for therapeutic interventions targeted at social dysfunction in these conditions., (© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Our coherent perception of external events is enabled by the integration of inputs from different senses occurring within a range of temporal offsets known as the temporal binding window (TBW), which varies from person to person. A relatively wide TBW may increase the likelihood that stimuli originating from different environmental events are erroneously integrated and abnormally large TBW has been found in psychiatric disorders characterized by unusual perceptual experiences. Despite strong evidence of inter-individual differences in TBW, both within clinical and nonclinical populations, the neurobiological underpinnings of this variability remain unclear. We adopted an integrated strategy linking TBW to temporal dynamics in functional magnetic resonance imaging (fMRI)-resting-state activity and cortical excitation/inhibition (E/I) balance. E/I balance was indexed by glutamate/Gamma-AminoButyric Acid (GABA) concentrations and common variation in glutamate and GABA genes in a healthy sample. Stronger resting-state long-range temporal correlations, indicated by larger power law exponent (PLE), in the auditory cortex, robustly predicted narrower audio-tactile TBW, which was in turn associated with lower cognitive-perceptual schizotypy. Furthermore, PLE was highest and TBW narrowest for individuals with intermediate levels of E/I balance, with shifts towards either extreme resulting in reduced multisensory temporal precision and increased schizotypy, effectively forming a neural "tuning curve" for multisensory experience and schizophrenia risk. Our findings shed light on the neurobiological underpinnings of multisensory integration and its potentially clinically relevant inter-individual variability., (© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype., (Copyright © 2017. Published by Elsevier B.V.)