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

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

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

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

Daily and intermittent smoking are associated with low prefrontal volume and low concentrations of prefrontal glutamate, creatine, myo-inositol, and N-acetylaspartate.

Cigarette smoking is still the largest contributor to disease and death worldwide. Successful cessation is hindered by decreases in prefrontal glutamate concentrations and gray matter volume due to daily smoking. Because nondaily, intermittent smoking also contributes greatly to disease and death, understanding whether infrequent tobacco use is associated with reductions in prefrontal glutamate concentrations and gray matter volume may aid public health. Eighty-five young participants (41 nonsmokers, 24 intermittent smokers, 20 daily smokers, mean age ~23 years old), underwent 1 H-magnetic resonance spectroscopy of the medial prefrontal cortex, as well as structural magnetic resonance imaging (MRI) to determine whole-brain gray matter volume. Compared with nonsmokers, both daily and intermittent smokers exhibited lower concentrations of glutamate, creatine, N-acetylaspartate, and myo-inositol in the medial prefrontal cortex, and lower gray matter volume in the right inferior frontal gyrus; these measures of prefrontal metabolites and structure did not differ between daily and intermittent smokers. Finally, medial prefrontal metabolite concentrations and right inferior frontal gray matter volume were positively correlated, but these relationships were not influenced by smoking status. This study provides the first evidence that both daily and intermittent smoking are associated with low concentrations of glutamate, creatine, N-acetylaspartate, and myo-inositol and low gray matter volume in the prefrontal cortex. Future tobacco cessation efforts should not ignore potential deleterious effects of intermittent smoking by considering only daily smokers. Finally, because low glutamate concentrations hinder cessation, treatments that can normalize tonic levels of prefrontal glutamate, such as N-acetylcysteine, may help intermittent and daily smokers to quit.

Reduced cortical GABA and glutamate in high schizotypy.

RATIONALE: Abnormal functioning of the inhibitory gamma-aminobutyric acid (GABA) and excitatory (glutamate) systems is proposed to play a role in the development of schizophrenia spectrum disorder. Although results are mixed, previous 1H-magnetic resonance spectroscopy (MRS) studies in schizophrenia and clinical high-risk samples report these metabolites are altered in comparison to healthy controls. Currently, however, there are few studies of these metabolites in schizotypy samples, a personality dimension associated with the experience of schizophrenia and psychosis-like symptoms. OBJECTIVES: We investigated if GABA and glutamate metabolite concentrations are altered in people with high schizotypy. We also explored the relationship between resilience to stress, GABA metabolite concentrations and schizotypy. METHODS: We used MRS to examine GABA and glutamate levels in the medial prefrontal cortex in people with low and high schizotypy traits as assessed with the Schizotypal Personality Questionnaire. Resilience to stress was assessed using the Connor-Davidson Resilience Scale. RESULTS: Compared to individuals with low schizotypy traits, high schizotypy individuals showed lower cortical prefrontal GABA (F (1,38) = 5.18, p = 0.03, η2 = 0.09) and glutamate metabolite levels (F (1, 49) = 6.25, p = 0.02, η2 = 0.02). Furthermore, participants with high GABA and high resilience levels were significantly more likely to be in the low schizotypy group than participants with low GABA and high resilience or high GABA and low resilience (95% CI 1.07-1.34, p < .001). CONCLUSIONS: These findings demonstrate that subclinical schizotypal traits are associated with abnormal functioning of both inhibitory and excitatory systems and suggest that these transmitters are implicated in a personality trait believed to be on a continuum with psychosis.

Relationship between depression, prefrontal creatine and grey matter volume.

BACKGROUND: Depression and low mood are leading contributors to disability worldwide. Research indicates that clinical depression may be associated with low creatine concentrations in the brain and low prefrontal grey matter volume. Because subclinical depression also contributes to difficulties in day-to-day life, understanding the neural mechanisms of depressive symptoms in all individuals, even at a subclinical level, may aid public health. METHODS: Eighty-four young adult participants completed the Depression, Anxiety and Stress Scale (DASS) to quantify severity of depression, anxiety and stress, and underwent 1H-Magnetic Resonance Spectroscopy of the medial prefrontal cortex and structural magnetic resonance imaging (MRI) to determine whole-brain grey matter volume. RESULTS/OUTCOMES: DASS depression scores were negatively associated (a) with concentrations of creatine (but not other metabolites) in the prefrontal cortex and (b) with grey matter volume in the right superior medial frontal gyrus. Medial prefrontal creatine concentrations and right superior medial frontal grey matter volume were positively correlated. DASS anxiety and DASS stress scores were not related to prefrontal metabolite concentrations or whole-brain grey matter volume. CONCLUSIONS/INTERPRETATIONS: This study provides preliminary evidence from a representative group of individuals who exhibit a range of depression levels that prefrontal creatine and grey matter volume are negatively associated with depression. While future research is needed to fully understand this relationship, these results provide support for previous findings, which indicate that increasing creatine concentrations in the prefrontal cortex may improve mood and well-being.

Impaired processing of threat in psychopathy: A systematic review and meta-analysis of factorial data in male offender populations.

BACKGROUND: Psychopathy is a personality disorder characterised by two underlying factors. Factor 1 (affective and interpersonal deficits) captures affective deficits, whilst Factor 2 (antisocial and impulsive/disorganised behaviours) captures life course persistent antisocial behaviours. Impaired processing of threat has been proposed as an aetiologically salient factor in the development of psychopathy, but the relationship of this impairment to the factorial structure of the disorder in adult male offenders is unclear. OBJECTIVES: To investigate whether threat processing deficits are characteristic of psychopathy as a unitary construct or whether such deficits are specifically linked to higher scores on individual factors. DATA SOURCES: A systematic review of the literature was conducted by searching PubMed, Web of Science and PsycINFO. METHODS: Studies were included if they (1) reported physiological measures of threat response as the primary outcome measure (2) indexed psychopathy using a well-validated clinician rated instrument such as the PCL-R (3) investigated male offenders between 18 and 60 years of age (4) reported threat processing analyses using both Factor 1 and Factor 2 scores (5) provided sufficient data to calculate effect sizes and (6) were published in English-language peer-reviewed journals. We identified twelve studies with data on 1112 participants for the meta-analysis of the relationship with Factor 1 scores, and nine studies with data on 801 participants for the meta-analysis of the relationship with Factor 2 scores. We conducted the meta-analyses to calculate correlations using random-effects models. RESULTS: PCL-R/SV Factor 1 scores were significantly and negatively related to threat processing indices (r = -0.22, (95%CI [-0.28, -.017]). Neither PCL-R/SV Factor 2 scores (r = -0.005, 95%CI [-0.10, 0.09]), nor PCL-R total score (r = -0.05, (95%CI [-0.15, -0.04]) were related to threat processing indices. No significant heterogeneity was detected for the Factor score results. CONCLUSIONS: The meta-analyses of the distinct psychopathy factors suggest that the threat processing deficits observed in male offenders with psychopathy are significantly associated with higher scores on Factor 1. A similar relationship does not exist with Factor 2 scores. Our findings highlight the importance of investigating the potentially discrete relationships between aetiological variables and the two factor constructs in the disorder.

Emerging Temporal Lobe Dysfunction in People at Clinical High Risk for Psychosis.

Clinical high-risk (CHR) individuals have been increasingly utilized to investigate the prodromal phases of psychosis and progression to illness. Research has identified medial and lateral temporal lobe abnormalities in CHR individuals. Dysfunction in the medial temporal lobe, particularly the hippocampus, is linked to dysregulation of glutamate and dopamine via a hippocampal-striatal-midbrain network that may lead to aberrant signaling of salience underpinning the formation of delusions. Similarly, lateral temporal dysfunction may be linked to the disorganized speech and language impairments observed in the CHR stage. Here, we summarize the significance of these neurobiological findings in terms of emergent psychotic symptoms and conversion to psychosis in CHR populations. We propose key questions for future work with the aim to identify the neural mechanisms that underlie the development of psychosis.