The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Robust associations between white matter microstructure and general intelligence.

Few tract-based spatial statistics (TBSS) studies have investigated the relations between intelligence and white matter microstructure in healthy (young) adults, and those have yielded mixed observations, yet white matter is fundamental for efficient and accurate information transfer throughout the human brain. We used a multicenter approach to identify white matter regions that show replicable structure-function associations, employing data from 4 independent samples comprising over 2000 healthy participants. TBSS indicated 188 voxels exhibited significant positive associations between g factor scores and fractional anisotropy (FA) in all 4 data sets. Replicable voxels formed 3 clusters, located around the left-hemispheric forceps minor, superior longitudinal fasciculus, and cingulum-cingulate gyrus with extensions into their surrounding areas (anterior thalamic radiation, inferior fronto-occipital fasciculus). Our results suggested that individual differences in general intelligence are robustly associated with white matter FA in specific fiber bundles distributed across the brain, consistent with the Parieto-Frontal Integration Theory of intelligence. Three possible reasons higher FA values might create links with higher g are faster information processing due to greater myelination, more direct information processing due to parallel, homogenous fiber orientation distributions, or more parallel information processing due to greater axon density.

Obsessive compulsive symptom dimensions are linked to altered white-matter microstructure in a community sample of youth.

Obsessive-compulsive symptoms (OCS) are common in school-aged children and predict the development of obsessive compulsive disorder (OCD). White-matter abnormalities have been described in OCD, but the white matter correlates of OCS in the developing brain are unclear. Some correlates of OCS (or a diagnosis of OCD) may reflect correlates of a transdiagnostic or even general psychopathology factor. We examined these questions in a large sample of typically developing youth (N = 1208), using a hierarchical analysis of fixel-based white matter measures in relation to OCS and general psychopathology. General psychopathology was associated with abnormalities in the posterior corpus callosum and forceps major in an age-dependent manner, suggesting altered maturation (specifically, hypermaturation in younger subjects). A unidimensional measure of OCS did not associate with any white-matter abnormalities, but analysis of separate OCS dimensions (derived from factor analysis within this sample) revealed the 'Bad Thoughts' dimension to associate with white-matter abnormalities in dorsal parietal white-matter and descending corticospinal tracts, and the 'Symmetry' dimension to associate with abnormalities in the anterior corpus callosum. Repetition/checking and Symmetry OCS were additionally associated with posterior abnormalities overlapping with the correlates of general psychopathology. Contamination symptoms had no white-matter correlates. Secondary analysis of fractional anisotropy (FA) revealed distinct white-matter abnormalities, suggesting that fixel-based and FA analyses identify distinct features of white matter relevant to psychopathology. These findings suggest that OCS dimensions correlate with dissociable abnormalities in white matter, implicating separable networks. Future studies should examine these white-matter signatures in a longitudinal framework.

The thalamus and its subnuclei-a gateway to obsessive-compulsive disorder.

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status.

Apophenia as the disposition to false positives: A unifying framework for openness and psychoticism.

Positive symptoms of schizophrenia and its extended phenotype-often termed psychoticism or positive schizotypy-are characterized by the inclusion of novel, erroneous mental contents. One promising framework for explaining positive symptoms involves apophenia, conceptualized here as a disposition toward false-positive errors. Apophenia and positive symptoms have shown relations to openness to experience (more specifically, to the openness aspect of the broader openness/intellect domain), and all of these constructs involve tendencies toward pattern seeking. Nonetheless, few studies have investigated the relations between psychoticism and non-self-report indicators of apophenia, let alone the role of normal personality variation. The current research used structural equation models to test associations between psychoticism, openness, intelligence, and non-self-report indicators of apophenia comprising false-positive error rates on a variety of computerized tasks. In Sample 1, 1,193 participants completed digit identification, theory of mind, and emotion recognition tasks. In Sample 2, 195 participants completed auditory signal detection and semantic word association tasks. Psychoticism and the openness aspect were positively correlated. Self-reported psychoticism, openness, and their shared variance were positively associated with apophenia, as indexed by false-positive error rates, whether or not intelligence was controlled for. Apophenia was not associated with other personality traits, and openness and psychoticism were not associated with false-negative errors. Findings provide insights into the measurement of apophenia and its relation to personality and psychopathology. Apophenia and pattern seeking may be promising constructs for unifying the openness aspect of personality with the psychosis spectrum and for providing an explanation of positive symptoms. Results are discussed in the context of possible adaptive characteristics of apophenia as well as potential risk factors for the development of psychotic disorders. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Toward a Neural Model of the Openness-Psychoticism Dimension: Functional Connectivity in the Default and Frontoparietal Control Networks.

Psychosis proneness has been linked to heightened Openness to Experience and to cognitive deficits. Openness and psychotic disorders are associated with the default and frontoparietal networks, and the latter network is also robustly associated with intelligence. We tested the hypothesis that functional connectivity of the default and frontoparietal networks is a neural correlate of the openness-psychoticism dimension. Participants in the Human Connectome Project (N = 1003) completed measures of psychoticism, openness, and intelligence. Resting state functional magnetic resonance imaging was used to identify intrinsic connectivity networks. Structural equation modeling revealed relations among personality, intelligence, and network coherence. Psychoticism, openness, and especially their shared variance were related positively to default network coherence and negatively to frontoparietal coherence. These associations remained after controlling for intelligence. Intelligence was positively related to frontoparietal coherence. Research suggests that psychoticism and openness are linked in part through their association with connectivity in networks involving experiential simulation and cognitive control. We propose a model of psychosis risk that highlights roles of the default and frontoparietal networks. Findings echo research on functional connectivity in psychosis patients, suggesting shared mechanisms across the personality-psychopathology continuum.

Connectivity-enhanced diffusion analysis reveals white matter density disruptions in first episode and chronic schizophrenia.

Reduced fractional anisotropy (FA) is a well-established correlate of schizophrenia, but it remains unclear whether these tensor-based differences are the result of axon damage and/or organizational changes and whether the changes are progressive in the adult course of illness. Diffusion MRI data were collected in 81 schizophrenia patients (54 first episode and 27 chronic) and 64 controls. Analysis of FA was combined with "fixel-based" analysis, the latter of which leverages connectivity and crossing-fiber information to assess both fiber bundle density and organizational complexity (i.e., presence and magnitude of off-axis diffusion signal). Compared with controls, patients with schizophrenia displayed clusters of significantly lower FA in the bilateral frontal lobes, right dorsal centrum semiovale, and the left anterior limb of the internal capsule. All FA-based group differences overlapped substantially with regions containing complex fiber architecture. FA within these clusters was positively correlated with principal axis fiber density, but inversely correlated with both secondary/tertiary axis fiber density and voxel-wise fiber complexity. Crossing fiber complexity had the strongest (inverse) association with FA (r = -0.82). When crossing fiber structure was modeled in the MRtrix fixel-based analysis pipeline, patients exhibited significantly lower fiber density compared to controls in the dorsal and posterior corpus callosum (central, postcentral, and forceps major). Findings of lower FA in patients with schizophrenia likely reflect two inversely related signals: reduced density of principal axis fiber tracts and increased off-axis diffusion sources. Whereas the former confirms at least some regions where myelin and or/axon count are lower in schizophrenia, the latter indicates that the FA signal from principal axis fiber coherence is broadly contaminated by macrostructural complexity, and therefore does not necessarily reflect microstructural group differences. These results underline the need to move beyond tensor-based models in favor of acquisition and analysis techniques that can help disambiguate different sources of white matter disruptions associated with schizophrenia.

White matter correlates of psychosis-linked traits support continuity between personality and psychopathology.

The link between diagnoses of psychotic disorders and attenuated white matter connectivity is well established, but little is known about the degree to which similar white matter differences predict traits linked to psychosis-proneness in the general population. Moreover, intelligence is too rarely considered as a covariate in neural endophenotype studies, despite its known protective role against psychopathology in general and its associations with broad aspects of neural structure and function. To determine whether psychosis-linked personality traits are linearly associated with white matter microstructure, we examined white matter correlates of Psychoticism, Absorption, and Openness to Experience in a large community sample, covarying for sex, age, and IQ. Findings support our hypothesis that the white matter correlates of the shared variance of these traits overlap substantially with the frontal lobe white matter connectivity patterns characteristic of psychotic spectrum disorders. These findings provide biological support for the notion that liability to psychosis is distributed throughout the population, is evident in brain structure, and manifests as normal personality variation at subclinical levels. (PsycINFO Database Record

Openness to Experience and Intellect Differentially Predict Creative Achievement in the Arts and Sciences.

The Big Five personality dimension Openness/Intellect is the trait most closely associated with creativity and creative achievement. Little is known, however, regarding the discriminant validity of its two aspects-Openness to Experience (reflecting cognitive engagement with perception, fantasy, aesthetics, and emotions) and Intellect (reflecting cognitive engagement with abstract and semantic information, primarily through reasoning)-in relation to creativity. In four demographically diverse samples totaling 1,035 participants, we investigated the independent predictive validity of Openness and Intellect by assessing the relations among cognitive ability, divergent thinking, personality, and creative achievement across the arts and sciences. We confirmed the hypothesis that whereas Openness predicts creative achievement in the arts, Intellect predicts creative achievement in the sciences. Inclusion of performance measures of general cognitive ability and divergent thinking indicated that the relation of Intellect to scientific creativity may be due at least in part to these abilities. Lastly, we found that Extraversion additionally predicted creative achievement in the arts, independently of Openness. Results are discussed in the context of dual-process theory.

Functional coherence of insula networks is associated with externalizing behavior.

The externalizing spectrum encompasses a range of maladaptive behaviors, including substance-use problems, impulsivity, and aggression. Although previous literature has linked externalizing behaviors with prefrontal and amygdala abnormalities, recent studies suggest insula functionality is implicated. This study investigated the relation between insula functional coherence and externalizing in a large community sample (N = 244). Participants underwent a resting functional MRI scan. Three nonartifactual intrinsic connectivity networks (ICNs) substantially involving the insula were identified after completing independent components analysis. Three externalizing domains-general disinhibition, substance abuse, and callous aggression-were measured with the Externalizing Spectrum Inventory. Regression models tested whether within-network coherence for the 3 insula ICNs was related to each externalizing domain. Posterior insula coherence was positively associated with general disinhibition and substance abuse. Anterior insula/ventral striatum/anterior cingulate network coherence was negatively associated with general disinhibition. Insula coherence did not relate to the callous aggression domain. Follow-up analyses indicated specificity for insula ICNs in their relation to general disinhibition and substance abuse as compared with other frontal and limbic ICNs. This study found insula network coherence was significantly associated with externalizing behaviors in community participants. Frontal and limbic ICNs containing less insular cortex were not related to externalizing. Thus, the neural synchrony of insula networks may be central for understanding externalizing psychopathology.

Subcortical intelligence: caudate volume predicts IQ in healthy adults.

This study examined the association between size of the caudate nuclei and intelligence. Based on the central role of the caudate in learning, as well as neuroimaging studies linking greater caudate volume to better attentional function, verbal ability, and dopamine receptor availability, we hypothesized the existence of a positive association between intelligence and caudate volume in three large independent samples of healthy adults (total N = 517). Regression of IQ onto bilateral caudate volume controlling for age, sex, and total brain volume indicated a significant positive correlation between caudate volume and intelligence, with a comparable magnitude of effect across each of the three samples. No other subcortical structures were independently associated with IQ, suggesting a specific biological link between caudate morphology and intelligence.

"They who dream by day": parallels between Openness to Experience and dreaming.

Individuals high in the personality trait Openness to Experience appear to engage spontaneously (during wake) in processes of elaborative encoding similar to those Llewellyn identifies in both dreaming and the ancient art of memory (AAOM). Links between Openness and dreaming support the hypothesis that dreaming is part of a larger process of cognitive exploration that facilitates adaptation to new experiences.

A novel differential susceptibility gene: CHRNA4 and moderation of the effect of maltreatment on child personality.

BACKGROUND: The differential susceptibility hypothesis states that some genetic variants that confer risk in adverse environments are beneficial in normal or nurturing environments. The cholinergic system is promising as a source of susceptibility genes because of its involvement in learning and neural plasticity. The cholinergic receptor gene CHRNA4 has been linked to characteristics related to the personality traits Neuroticism and Openness/Intellect. METHODS: The effects of interaction between CHRNA4 genotype and maltreatment status on child personality were examined in a well matched sample of 339 maltreated and 275 non-maltreated children (aged 8-13 years). RESULTS: Variation in CHRNA4 interacted with childhood maltreatment to predict personality in a manner indicating differential susceptibility. The interaction of CHRNA4 and maltreatment status predicted Neuroticism and Openness/Intellect. Maltreated children with the rs1044396 T/T genotype scored highest on Neuroticism and showed no effect of genotype on Openness/Intellect. Non-maltreated children with this genotype scored lowest on Neuroticism and highest on Openness/Intellect. CONCLUSION: Variation in CHRNA4 appears to contribute to personality by affecting degree of developmental sensitivity to both normal and adverse environments.

Cortical thickness and subcortical gray matter reductions in neuropsychiatric systemic lupus erythematosus.

Within systemic lupus erythematosus (SLE) patients can be divided into groups with and without central nervous system involvement, the latter being subcategorized as neuropsychiatric systemic lupus erythematosus (NPSLE). While a number of research groups have investigated NPSLE, there remains a lack of consistent application of this diagnostic criteria within neuroimaging studies. Previous neuroimaging research suggests that SLE patients have reduced subcortical and regional gray matter volumes when compared to controls, and that these group differences may be driven by SLE patients with neuropsychiatric symptoms. The current study sought to compare measures of cortical thickness and subcortical structure volume between NPSLE, SLE, and healthy controls. We hypothesized that patients with NPSLE (N = 21) would have thinner cortex and reduced subcortical gray matter volumes when compared to SLE (N = 16) and control subjects (N = 21). All subjects underwent MRI examinations on a 1.5 Tesla Siemens Sonata scanner. Anatomical reconstruction and segmentation were performed using the FreeSurfer image analysis suite. Cortical and subcortical volumes were extracted from FreeSurfer and analyzed for group differences, controlling for age. The NPSLE group exhibited decreased cortical thickness in clusters of the left frontal and parietal lobes as well as in the right parietal and occipital lobes compared to control subjects. Compared to the SLE group, the NPSLE group exhibited comparable thinning in clusters of the frontal and temporal lobes. Controlling for age, we found that between group effects for subcortical gray matter structures were significant for the thalamus (F = 3.06, p = .04), caudate nucleus (F = 3.19, p = .03), and putamen (F = 4.82, p = .005). These results clarify previous imaging work identifying cortical atrophy in a mixed SLE and NPSLE group, and suggest that neuroanatomical abnormalities are specific to SLE patients diagnosed with neuropsychiatric symptoms. Future work should help elucidate the underlying mechanisms underlying the emerging neurobiological profile seen in NPSLE, as well as clarify the apparent lack of overlap between cortical thinning and functional activation results and other findings pointing to increased functional activation during cognitive tasks.