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.

Contributions of Parasympathetic Arousal-Related Activity to Cognitive Performance in Patients With First-Episode Psychosis and Control Subjects.

BACKGROUND: Cognitive impairment is integral to the pathophysiology of psychosis. Recent findings implicate autonomic arousal-related activity in both momentary fluctuations and individual differences in cognitive performance. Although altered autonomic arousal is common in patients with first-episode psychosis (FEP), its contribution to cognitive performance is unknown. METHODS: A total of 24 patients with FEP (46% male, age = 24.31 [SD 4.27] years) and 24 control subjects (42% male, age = 27.06 [3.44] years) performed the Multi-Source Interference Task in-scanner with simultaneous pulse oximetry. First-level models included the cardiac-blood oxygen level-dependent regressor, in addition to task (congruent, interference, and error) and nuisance (motion and CompCor physiology) regressors. The cardiac-blood oxygen level-dependent regressor reflected parasympathetic arousal-related activity and was created by convolving the interbeat interval at each heartbeat with the hemodynamic response function. Group models examined the effect of group or cognitive performance (reaction times × error rate) on arousal-related and task activity, while controlling for sex, age, and framewise displacement. RESULTS: Parasympathetic arousal-related activity was robust in both groups but localized to different regions for patients with FEP and healthy control subjects. Within both groups, arousal-related activity was significantly associated with cognitive performance across occipital and temporal cortical regions. Greater arousal-related activity in the bilateral prefrontal cortex (Brodmann area 9) was related to better performance in healthy control subjects but not patients with FEP. CONCLUSIONS: Autonomic arousal circuits contribute to cognitive performance and the pathophysiology of FEP. Arousal-related functional activity is a novel indicator of cognitive ability and should be incorporated into neurobiological models of cognition in psychosis.

Frontal lobe fALFF measured from resting-state fMRI as a prognostic biomarker in first-episode psychosis.

Clinical response to antipsychotic drug treatment is highly variable, yet prognostic biomarkers are lacking. The goal of the present study was to test whether the fractional amplitude of low-frequency fluctuations (fALFF), as measured from baseline resting-state fMRI data, can serve as a potential biomarker of treatment response to antipsychotics. Patients in the first episode of psychosis (n = 126) were enrolled in two prospective studies employing second-generation antipsychotics (risperidone or aripiprazole). Patients were scanned at the initiation of treatment on a 3T MRI scanner (Study 1, GE Signa HDx, n = 74; Study 2, Siemens Prisma, n = 52). Voxelwise fALFF derived from baseline resting-state fMRI scans served as the primary measure of interest, providing a hypothesis-free (as opposed to region-of-interest) search for regions of the brain that might be predictive of response. At baseline, patients who would later meet strict criteria for clinical response (defined as two consecutive ratings of much or very much improved on the CGI, as well as a rating of ≤3 on psychosis-related items of the BPRS-A) demonstrated significantly greater baseline fALFF in bilateral orbitofrontal cortex compared to non-responders. Thus, spontaneous activity in orbitofrontal cortex may serve as a prognostic biomarker of antipsychotic treatment.

Striatal functional connectivity in psychosis relapse: A hypothesis generating study.

Most individuals with psychotic disorders relapse over their course of illness, yet the neural processes that may lead to symptom worsening are poorly understood. Importantly, such processes could be potentially affected by antipsychotic adherence status upon relapse (i.e., relapse despite ongoing antipsychotic maintenance vs following antipsychotic discontinuation), reflecting distinct mechanisms. As a first foray into this question, we aim to compare the striatal connectivity index (SCI), a biomarker derived from striatal resting state functional connectivity predictive of treatment response, by adherence status upon relapse. In order to confirm adherence status upon relapse, we compared individuals treated with long-acting injectable antipsychotics upon relapse (i.e., breakthrough psychosis) (n = 23), with individuals who had decided to interrupt antipsychotic treatment and then relapsed (n = 27), as well as healthy controls (n = 26). We acquired for each individual >10 min of resting state fMRI, to generate functional connectivity maps. Region of interest (ROI) analyses were conducted to calculate SCI values for each participant. These values were entered as dependent variable in a linear regression adjusted for sex and age for which adherence status was the independent variable. Individuals in the breakthrough psychosis group had significantly lower SCI values than healthy controls (Cohen's d = 0.99, p < 0.001), and non-adherent individuals upon relapse (Cohen's d = 0.58, p = 0.032), whereas non-adherent individuals had also trend level lower SCI values than healthy controls (Cohen's d = 0.44, p = 0.09). These results suggest the hypothesis that striatal functional connectivity may be aberrant in psychosis relapse, and that this dysfunction may be greater among individuals who developed relapse despite ongoing antipsychotic treatment.

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.

The Role of Executive Function in Adolescent Adaptive Risk-Taking on the Balloon Analogue Risk Task.

The present study examined the role of executive control functions (ECF) in adaptive risk-taking during adolescence. Healthy individuals aged 8-25 were administered ECF measures and the Balloon Analogue Risk Task (BART), a computerized measure of risk-taking propensity. Findings demonstrated that adolescents who executed a more consistent response strategy evidenced better performance on the BART. Greater working memory (WM) predicted lower response variability and WM capacity mediated the relationship between age and variability. Results suggest that intra-individual response variability may index adaptive risk-taking and that the development of ECF, specifically WM, may play an integral role in adaptive decision making during adolescence and young adulthood.