Superior temporal sulcus folding, functional network connectivity, and autistic-like traits in a non-clinical population.

BACKGROUND: Autistic-like traits (ALT) are prevalent across the general population and might be linked to some facets of a broader autism spectrum disorder (ASD) phenotype. Recent studies suggest an association of these traits with both genetic and brain structural markers in non-autistic individuals, showing similar spatial location of findings observed in ASD and thus suggesting a potential neurobiological continuum. METHODS: In this study, we first tested an association of ALTs (assessed with the AQ questionnaire) with cortical complexity, a cortical surface marker of early neurodevelopment, and then the association with disrupted functional connectivity. We analysed structural T1-weighted and resting-state functional MRI scans in 250 psychiatrically healthy individuals without a history of early developmental disorders, in a first step using the CAT12 toolbox for cortical complexity analysis and in a second step we used regional cortical complexity findings to apply the CONN toolbox for seed-based functional connectivity analysis. RESULTS: Our findings show a significant negative correlation of both AQ total and AQ attention switching subscores with left superior temporal sulcus (STS) cortical folding complexity, with the former being significantly correlated with STS to left lateral occipital cortex connectivity, while the latter showed significant positive correlation of STS to left inferior/middle frontal gyrus connectivity (n = 233; all p < 0.05, FWE cluster-level corrected). Additional analyses also revealed a significant correlation of AQ attention to detail subscores with STS to left lateral occipital cortex connectivity. LIMITATIONS: Phenotyping might affect association results (e.g. choice of inventories); in addition, our study was limited to subclinical expressions of autistic-like traits. CONCLUSIONS: Our findings provide further evidence for biological correlates of ALT even in the absence of clinical ASD, while establishing a link between structural variation of early developmental origin and functional connectivity.

Larger putamen in individuals at risk and with manifest bipolar disorder.

BACKGROUND: Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations. METHODS: In 410 male and female participants aged 17-35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPIbipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites. RESULTS: Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake. CONCLUSIONS: Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.

Multi-modal morphometric association study of subclinical depressive symptoms using voxel-based morphometry, cortical thickness, and diffusion tensor imaging (DTI).

BACKGROUND: Case-control studies in major depression have established numerous regional grey and white matter effects in fronto-limbic brain regions. Yet, brain structural studies of dimensional depressive psychopathology within the subclinical spectrum are still limited, in particular for multi-modal imaging approaches. METHODS: Using voxel-based and surface-based morphometry (cortical thickness) in combination with diffusion tensor imaging (DTI) in a large non-clinical sample (N = 300), we correlated grey and white matter structural variation with subclinical depressive symptoms assessed with Beck's Depression inventory (BDI). RESULTS: We found a significant decrease of axial diffusivity associated with higher BDI scores in the left hippocampal part of the cingulum bundle (p < 0.05, threshold free cluster enhanced [TFCE] p-value) and some grey matter trend results e.g., a non-linear negative correlation of cortical thickness with depressive symptom load in the right pre/postcentral cortex (pFWE = 0.054, family wise error [FWE] peak level corrected) and a trend in grey matter volume decrease in women in the inferior frontal gyrus (pFWE = 0.054). LIMITATIONS: Since all grey matter effects disappear after FWE correction, we assume more stable effects in a larger, less homogenous sample enriched by help-seeking subjects covering a wider range of subclinical psychopathology. CONCLUSION: Our study adds correlations between single depressive symptoms and brain structure to a growing literature. Since subclinical depression is increasingly recognised to be relevant in our understanding of manifest depression, early detection and identification of potential brain correlates of minor depressive symptoms has the potential to expand and reveal possible biomarkers and early psychological treatment.

Structural brain abnormalities and aggressive behaviour in schizophrenia: Mega-analysis of data from 2095 patients and 2861 healthy controls via the ENIGMA consortium.

Background: Schizophrenia is associated with an increased risk of aggressive behaviour, which may partly be explained by illness-related changes in brain structure. However, previous studies have been limited by group-level analyses, small and selective samples of inpatients and long time lags between exposure and outcome. Methods: This cross-sectional study pooled data from 20 sites participating in the international ENIGMA-Schizophrenia Working Group. Sites acquired T1-weighted and diffusion-weighted magnetic resonance imaging scans in a total of 2095 patients with schizophrenia and 2861 healthy controls. Measures of grey matter volume and white matter microstructural integrity were extracted from the scans using harmonised protocols. For each measure, normative modelling was used to calculate how much patients deviated (in z-scores) from healthy controls at the individual level. Ordinal regression models were used to estimate the associations of these deviations with concurrent aggressive behaviour (as odds ratios [ORs] with 99% confidence intervals [CIs]). Mediation analyses were performed for positive symptoms (i.e., delusions, hallucinations and disorganised thinking), impulse control and illness insight. Aggression and potential mediators were assessed with the Positive and Negative Syndrome Scale, Scale for the Assessment of Positive Symptoms or Brief Psychiatric Rating Scale. Results: Aggressive behaviour was significantly associated with reductions in total cortical volume (OR [99% CI] = 0.88 [0.78, 0.98], p = .003) and global white matter integrity (OR [99% CI] = 0.72 [0.59, 0.88], p = 3.50 × 10-5) and additional reductions in dorsolateral prefrontal cortex volume (OR [99% CI] = 0.85 [0.74, 0.97], p =.002), inferior parietal lobule volume (OR [99% CI] = 0.76 [0.66, 0.87], p = 2.20 × 10-7) and internal capsule integrity (OR [99% CI] = 0.76 [0.63, 0.92], p = 2.90 × 10-4). Except for inferior parietal lobule volume, these associations were largely mediated by increased severity of positive symptoms and reduced impulse control. Conclusions: This study provides evidence that the co-occurrence of positive symptoms, poor impulse control and aggressive behaviour in schizophrenia has a neurobiological basis, which may inform the development of therapeutic interventions.

Brain Structural Network Connectivity of Formal Thought Disorder Dimensions in Affective and Psychotic Disorders.

BACKGROUND: The psychopathological syndrome of formal thought disorder (FTD) is not only present in schizophrenia (SZ), but also highly prevalent in major depressive disorder and bipolar disorder. It remains unknown how alterations in the structural white matter connectome of the brain correlate with psychopathological FTD dimensions across affective and psychotic disorders. METHODS: Using FTD items of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, we performed exploratory and confirmatory factor analyses in 864 patients with major depressive disorder (n= 689), bipolar disorder (n = 108), or SZ (n = 67) to identify psychopathological FTD dimensions. We used T1- and diffusion-weighted magnetic resonance imaging to reconstruct the structural connectome of the brain. To investigate the association of FTD subdimensions and global structural connectome measures, we employed linear regression models. We used network-based statistic to identify subnetworks of white matter fiber tracts associated with FTD symptomatology. RESULTS: Three psychopathological FTD dimensions were delineated, i.e., disorganization, emptiness, and incoherence. Disorganization and incoherence were associated with global dysconnectivity. Network-based statistics identified subnetworks associated with the FTD dimensions disorganization and emptiness but not with the FTD dimension incoherence. Post hoc analyses on subnetworks did not reveal diagnosis × FTD dimension interaction effects. Results remained stable after correcting for medication and disease severity. Confirmatory analyses showed a substantial overlap of nodes from both subnetworks with cortical brain regions previously associated with FTD in SZ. CONCLUSIONS: We demonstrated white matter subnetwork dysconnectivity in major depressive disorder, bipolar disorder, and SZ associated with FTD dimensions that predominantly comprise brain regions implicated in speech. Results open an avenue for transdiagnostic, psychopathology-informed, dimensional studies in pathogenetic research.

Modelling the overlap and divergence of autistic and schizotypal traits on hippocampal subfield volumes and regional cerebral blood flow.

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.

Data-driven multivariate identification of gyrification patterns in a transdiagnostic patient cohort: A cluster analysis approach.

BACKGROUND: Multivariate data-driven statistical approaches offer the opportunity to study multi-dimensional interdependences between a large set of biological parameters, such as high-dimensional brain imaging data. For gyrification, a putative marker of early neurodevelopment, direct comparisons of patterns among multiple psychiatric disorders and investigations of potential heterogeneity of gyrification within one disorder and a transdiagnostic characterization of neuroanatomical features are lacking. METHODS: In this study we used a data-driven, multivariate statistical approach to analyze cortical gyrification in a large cohort of N = 1028 patients with major psychiatric disorders (Major depressive disorder: n = 783, bipolar disorder: n = 129, schizoaffective disorder: n = 44, schizophrenia: n = 72) to identify cluster patterns of gyrification beyond diagnostic categories. RESULTS: Cluster analysis applied on gyrification data of 68 brain regions (DK-40 atlas) identified three clusters showing difference in overall (global) gyrification and minor regional variation (regions). Newly, data-driven subgroups are further discriminative in cognition and transdiagnostic disease risk factors. CONCLUSIONS: Results indicate that gyrification is associated with transdiagnostic risk factors rather than diagnostic categories and further imply a more global role of gyrification related to mental health than a disorder specific one. Our findings support previous studies highlighting the importance of association cortices involved in psychopathology. Explorative, data-driven approaches like ours can help to elucidate if the brain imaging data on hand and its a priori applied grouping actually has the potential to find meaningful effects or if previous hypotheses about the phenotype as well as its grouping have to be revisited.

Structural connectivity of grandiose versus vulnerable narcissism as models of social dominance and subordination.

Social dominance and subordination have been linked to fronto-limbic and fronto-thalamic networks and are related to phenotypes such as grandiose vs. vulnerable narcissistic traits. The latter have been linked to clinical features such as empathy and emotional regulation. In this study we tested the hypotheses that narcissistic traits are associated with white matter integrity in fasciculus uncinate, cingulum, and anterior thalamic radiation (ATR). We applied the Pathological Narcissism Inventory (PNI) to assess narcissistic traits in a sample of 267 psychiatrically healthy individuals. We used 3 T MRI to acquire Diffusion Tensor Imaging data for analysis with TBSS in FSL applying TFCE to test for correlations of fractional anisotropy (FA) and PNI scales. We detected a significant positive correlation of PNI total and FA in the right posterior cingulum. PNI Vulnerability was significantly correlated with FA in the left anterior and right posterior cingulum. We did not find overall correlations with PNI Grandiosity, but additional analyses showed significant effects with FA of ATR. Our results strengthen network models for narcissism underlying both personality variation and pathology. Especially associations of narcissistic vulnerability within fronto-limbic tracts suggest overlaps within neural correlates of related phenotypes like neuroticism, social subordination, and negative emotionality.

Altered brain dynamic in major depressive disorder: state and trait features.

Temporal neural synchrony disruption can be linked to a variety of symptoms of major depressive disorder (MDD), including mood rigidity and the inability to break the cycle of negative emotion or attention biases. This might imply that altered dynamic neural synchrony may play a role in the persistence and exacerbation of MDD symptoms. Our study aimed to investigate the changes in whole-brain dynamic patterns of the brain functional connectivity and activity related to depression using the hidden Markov model (HMM) on resting-state functional magnetic resonance imaging (rs-fMRI) data. We compared the patterns of brain functional dynamics in a large sample of 314 patients with MDD (65.9% female; age (mean ± standard deviation): 35.9 ± 13.4) and 498 healthy controls (59.4% female; age: 34.0 ± 12.8). The HMM model was used to explain variations in rs-fMRI functional connectivity and averaged functional activity across the whole-brain by using a set of six unique recurring states. This study compared the proportion of time spent in each state and the average duration of visits to each state to assess stability between different groups. Compared to healthy controls, patients with MDD showed significantly higher proportional time spent and temporal stability in a state characterized by weak functional connectivity within and between all brain networks and relatively strong averaged functional activity of regions located in the somatosensory motor (SMN), salience (SN), and dorsal attention (DAN) networks. Both proportional time spent and temporal stability of this brain state was significantly associated with depression severity. Healthy controls, in contrast to the MDD group, showed proportional time spent and temporal stability in a state with relatively strong functional connectivity within and between all brain networks but weak averaged functional activity across the whole brain. These findings suggest that disrupted brain functional synchrony across time is present in MDD and associated with current depression severity.

Negative Stressful Life Events and Social Support Are Associated With White Matter Integrity in Depressed Patients and Healthy Control Participants: A Diffusion Tensor Imaging Study.

BACKGROUND: Negative stressful life events and deprivation of social support play critical roles in the development and maintenance of major depressive disorder (MDD). The present study aimed to investigate in a large sample of patients with MDD and healthy control participants (HCs) whether these effects are also reflected in white matter (WM) integrity. METHODS: In this diffusion tensor imaging study, 793 patients with MDD and 793 age- and sex-matched HCs were drawn from the Marburg-Münster Affective Disorders Cohort Study (MACS) and completed the Life Events Questionnaire (LEQ) and Social Support Questionnaire (SSQ). Generalized linear models were performed to test voxelwise associations between fractional anisotropy (FA) and diagnosis (analysis 1), LEQ (analysis 2), and SSQ (analysis 3). We examined whether SSQ interacts with LEQ on FA or is independently associated with improved WM integrity (analysis 4). RESULTS: Patients with MDD showed lower FA in several frontotemporal association fibers compared with HCs (pTFCE-FWE = .028). Across both groups, LEQ correlated negatively with FA in widely distributed WM tracts (pTFCE-FWE = .023), while SSQ correlated positively with FA in the corpus callosum (pTFCE-FWE = .043). Modeling the combined association of both variables on FA revealed significant-and antagonistic-main effects of LEQ (pTFCE-FWE = .031) and SSQ (pTFCE-FWE = .037), but no interaction of SSQ × LEQ. CONCLUSIONS: Our results indicate that negative stressful life events and social support are both related to WM integrity in opposing directions. The associations did not differ between patients with MDD and HCs, suggesting more general, rather than depression-specific, mechanisms. Furthermore, social support appears to contribute to improved WM integrity independent of stressful life events.

Trait schizotypy and the psychosis prodrome: Current standard assessment of extended psychosis spectrum phenotypes.

Schizotypy has become an increasingly important construct for elaborating psychotic disorders that vary along the schizophrenic spectrum. However, different schizotypy inventories vary in conceptual approach and measurement. In addition, commonly used schizotypy scales have been seen as qualitatively different from screening instruments for prodromal schizophrenia like the Prodromal Questionnaire-16 (PQ-16). Our study investigated the psychometric properties of three schizotypy questionnaires (the Schizotypal Personality Questionnaire-Brief, Oxford-Liverpool Inventory of Feelings and Experiences, and the Multidimensional Schizotypy Scale) as well as the PQ-16 in a cohort of 383 non-clinical subjects. We initially evaluated their factor structure using Principal Component Analysis (PCA) and used Confirmatory Factor Analysis (CFA) to test a newly proposed composition of factors. PCA results support a three-factor structure of schizotypy that accounts for 71 % of the total variance, but also shows cross-loadings of some schizotypy subscales. CFA of the newly composed schizotypy factors (together with an added neuroticism factor) shows good fit. Analyses including the PQ-16 indicate considerable overlap with measures of trait schizotypy, suggesting that the PQ-16 might not be quantitatively or qualitatively different from schizotypy measurements. Taken together, results indicate that there is good support for a three-factor structure of schizotypy but also that different schizotypy measurements grasp facets of schizotypy differently. This points towards the need for an integrative approach for assessing the construct of schizotypy.

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.

Associations of subclinical autistic-like traits with brain structural variation using diffusion tensor imaging and voxel-based morphometry.

BACKGROUND: Previous case-control studies of autistic spectrum disorder (ASD) have identified altered brain structure such as altered frontal and temporal cortex volumes, or decreased fractional anisotropy (FA) within the inferior fronto-occipital fasciculus in patients. It remains unclear whether subclinical autistic-like traits might also be related to variation in these brain structures. METHODS: In this study, we analyzed magnetic resonance imaging (MRI) data of 250 psychiatrically healthy subjects phenotyped for subclinical autistic-like traits using the Autism Spectrum Quotient (AQ). For data analysis, we used voxel-based morphometry of T1-MRIs (Computational Anatomy Toolbox) and tract-based spatial statistics for diffusion tensor imaging data. RESULTS: AQ attention switching subscale correlated negatively with FA values in the bilateral uncinate fasciculus as well as the bilateral inferior fronto-occipital fasciculus. Higher AQ attention switching subscale scores were associated with increased mean diffusivity and radial diffusivity values in the uncinate fasciculus, while axial diffusivity values within this tract show a negative correlation. AQ attention to detail subscale correlated positively with gray matter volume in the right pre- and postcentral gyrus. CONCLUSIONS: We demonstrate that individuals with higher levels of autism-spectrum-like features show decreased white matter integrity in tracts associated with higher-level visual processing and increased cortical volume in areas linked to movement sequencing and working memory. Our results resemble regional brain structure alterations found in individuals with ASD. This offers opportunities to further understand the etiology and pathogenesis of the disorder and shows a subclinical continuum perspective.

Subclinical schizotypal vs. autistic traits show overlapping and diametrically opposed facets in a non-clinical population.

BACKGROUND: The overlap of autism spectrum disorder (ASD) and psychosis or schizophrenia spectrum disorders (SSD) has exposed problems central to conceptualising and understanding co-morbidity in psychiatric disorders. METHODS: In the present study, we demonstrate that a deep phenotyping approach aids clarification of both overlapping and diametrically opposed features of ASD and SSD on the level of trait facets. RESULTS: We first show overlap of negative and disorganised (but not positive) features of schizotypy with autistic traits in a sample of n = 376 German non-clinical subjects using multiple psychometric measures of schizotypy (MSS multidimensional schizotypy scale, OLIFE Oxford-Liverpool Inventory of Feelings and Experiences, and SPQ-B schizotypal personality questionnaire - brief) and the AQ autism spectrum quotient, with control measures for affective spectrum pathology (BDI). Findings were then replicated in a French-Swiss sample (n = 264) using MSS, OLIFE, AQ, and in addition the Community Assessment of Psychic Experiences (CAPE). Additional principal component analysis confirmed our finding of the co-existence of both overlapping (loss of function, social communication deficit, and negative schizotypy) as well as diametrically opposed features (AQ attention to detail, positive schizotypy) across the two spectra. Results were validated with Horn's parallel analyses, affirming two component solutions, and PCA using sample-specific, factor-analysis-derived schizotypy scores. CONCLUSIONS: Providing a framework for multi-dimensional transdiagnostic characterisation of ASD vs. SSD phenotypes we point out overlapping vs. discriminating facets. In addition to the use of novel multidimensional schizotypy scales, it also shows transcultural consistency of findings, and highlights a particular role for the attention to detail AQ subscale.

Distress severity in perceptual anomalies moderates the relationship between prefrontal brain structure and psychosis proneness in nonclinical individuals.

In the general population, psychosis risk phenotypes occur independently of attenuated prodromal syndromes. Neurobiological correlates of vulnerability could help to understand their meaningfulness. Interactions between the occurrence of psychotic-like experiences (PLE) and other psychological factors e.g., distress related to PLE, may distinguish psychosis-prone individuals from those without risk of future psychotic disorder. We aimed to investigate whether (a) correlates of total PLE and distress, and (b) symptom dimension-specific moderation effects exist at the brain structural level in non-help-seeking adults reporting PLE below and above the screening criterion for clinical high-risk (CHR). We obtained T1-weighted whole-brain MRI scans from 104 healthy adults from the community without psychosis CHR states for voxel-based morphometry (VBM). Brain structural associations with PLE and PLE distress were analysed with multiple linear regression models. Moderation of PLE by distress severity of two types of positive symptoms from the Prodromal Questionnaire (PQ-16) screening inventory was explored in regions-of-interest after VBM. Total PQ-16 score was positively associated with grey matter volume (GMV) in prefrontal regions, occipital fusiform and lingual gyri (p < 0.05, FDR peak-level corrected). Overall distress severity and GMV were not associated. Examination of distress severity on the positive symptom dimensions as moderators showed reduced strength of the association between PLE and rSFG volume with increased distress severity for perceptual PLE. In this study, brain structural variation was related to PLE level, but not distress severity, suggesting specificity. In healthy individuals, positive relationships between PLE and prefrontal volumes may indicate protective features, which supports the insufficiency of PLE for the prediction of CHR. Additional indicators of vulnerability, such as distress associated with perceptual PLE, change the positive brain structure relationship. Brain structural findings may strengthen clinical objectives through disentanglement of innocuous and risk-related PLE.

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.

Cortical Gyrification, Psychotic-Like Experiences, and Cognitive Performance in Nonclinical Subjects.

BACKGROUND: Psychotic-like experiences (PLE) are present in nonclinical populations, yet their association with brain structural variation, especially markers of early neurodevelopment, is poorly understood. We tested the hypothesis that cortical surface gyrification, a putative marker of early brain development, is associated with PLE in healthy subjects. METHODS: We analyzed gyrification from 3 Tesla MRI scans (using CAT12 software) and PLE (positive, negative, and depressive symptom dimensions derived from the Community Assessment of Psychic Experiences, CAPE) in 103 healthy participants (49 females, mean age 29.13 ± 9.37 years). A subsample of 63 individuals completed tasks from the Wechsler Adult Intelligence Scale and Controlled Oral Word Association Test. Estimated IQ and a composite neuropsychological score were used to explore mediation pathways via cognition. RESULTS: Positive PLE distress was negatively associated with gyrification of the left precuneus. PLE depression dimension showed a negative association with gyrification in the right supramarginal and temporal region. There was no significant mediating effect of cognition on these associations. CONCLUSION: Our results support a neurobiological psychosis spectrum, for the first time linking an early developmental imaging marker (rather than volume) to dimensional subclinical psychotic symptoms. While schizophrenia risk, neurodevelopment, and cognitive function might share genetic risk factors, additional mediation analyses did not confirm a mediating effect of cognition on the gyrification-psychopathology correlation.

Efficacy of Systolic Extinction Training in Fibromyalgia Patients With Elevated Blood Pressure Response to Stress: A Tailored Randomized Controlled Trial.

OBJECTIVE: An intrinsic pain regulatory system is modulated by both cardiovascular dynamics that influence baroreflex sensitivity (BRS) and is diminished in fibromyalgia (FM). Baroreceptors relay cardiovascular output to the dorsal medial nucleus tractus solitarius reflex arcs that regulate pain, sleep, anxiety, and blood pressure. The aim of this study was to evaluate the effects of systolic extinction training (SET), which combines operant treatment (OT) with baroreflex training (BRT). BRT delivers peripheral electrical stimulation within a few milliseconds of the systolic or diastolic peak in the cardiac cycle. In addition, we compared SET to OT-transcutaneous electrical stimulation (TENS) independent of the cardiac cycle and aerobic exercise (AE)-BRT in FM patients with elevated blood pressure responses to stress. METHODS: Sixty-two female patients with FM were randomized to receive either SET (n = 21), OT-TENS (n = 20), or AE-BRT (n = 21). Outcome assessments were performed before treatment (T1), after 5 weeks of treatment (T2), and after the 12-month follow-up (T3). RESULTS: In contrast to patients receiving OT-TENS or AE-BRT, those receiving SET reported a significantly greater reduction in pain and pain interference (all P < 0.01) that was maintained at the 12-month follow-up. Clinically meaningful pain reduction at T3 was achieved in 82% of patients in the SET group, 39% of those in the OT-TENS group, and only 14% of those in the AE-BRT group. Patients in the SET group showed a significant increase (57%) in BRS following treatment, while neither the AE-BRT group or the OT-TENS group showed significant changes over time. CONCLUSION: SET resulted in statistically significant, clinically meaningful, and long-lasting pain remission and interference compared to OT-TENS and AE-BRT. These results suggest that BRS modification is the primary mechanism of improvement. Replication of our results using larger samples and extension to other chronic pain conditions appear to be warranted.