Childhood trauma moderates schizotypy-related brain morphology: analyses of 1182 healthy individuals from the ENIGMA schizotypy working group.

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.

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.

On the Correlations of Gray Matter with Schizotypy in Mentally Healthy Subjects.

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.

Neural bases of reward anticipation in healthy individuals with low, mid, and high levels of schizotypy.

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.

Gradients of striatal function in antipsychotic-free first-episode psychosis and schizotypy.

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.

Neural correlates of mental time travel in individuals with high level of schizotypy.

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.

Activation of the left medial temporal gyrus and adjacent brain areas during affective theory of mind processing correlates with trait schizotypy in a nonclinical population.

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.

Distinct neural signatures of schizotypy and psychopathy during visual word-nonword recognition.

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.

Frontotemporal thalamic connectivity in schizophrenia and schizotypal personality disorder.

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.

Classification of Low and High Schizotypy Levels via Evaluation of Brain Connectivity.

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.

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.

Structural and functional neural correlates of schizotypy: A systematic review.

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).

Schizotypy, childhood trauma and brain morphometry.

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.

Nonclinical psychotic-like experiences and schizotypy dimensions: Associations with hippocampal subfield and amygdala volumes.

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.

Altered cortico-striatal functional connectivity in people with high levels of schizotypy: A longitudinal resting-state study.

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.

Neural Correlates of Schizotypal Personality Disorder: A Systematic Review of Neuroimaging and EEG Studies.

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.

Anterior vs Posterior Hippocampal Subfields in an Extended Psychosis Phenotype of Multidimensional Schizotypy in a Nonclinical Sample.

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.

High schizotypy traits are associated with reduced hippocampal resting state functional connectivity.

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.

Orbitofrontal-Striatal Structural Alterations Linked to Negative Symptoms at Different Stages of the Schizophrenia Spectrum.

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.

Grey matter volume and structural covariance associated with schizotypy.

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.