Dimensions of psychosis: Elucidating the subclinical spectrum using neuroimaging markers

Psychosis unifies a collective of disorders characterised by symptom dimensions (Gaebel & Zielasek, 2015). Purposefully delimited clinical descriptors of schizophrenia spectrum and psychotic disorders (American Psychiatric Association, 2013) impose challenges on the identification of aetiological and clinically meaningful predictors. The disassembly of psychiatric diagnoses into their elementary symptom dimensions has helped formulate psychosis phenotypes fitted on a psychosis continuum (Verdoux & van Os, 2002). Aetiological models of psychosis may be studied through schizotypy and transient psychotic experiences (Barrantes-Vidal et al., 2015; Nelson, Fusar-Poli, & Yung, 2012), collectively termed subclinical psychosis phenotypes. The dimensional psychometric structures of these phenotypes varying in temporal stability (Linscott & van Os, 2013; Mason et al., 1995; Stefanis et al., 2002), and their implications might be further consolidated when paired with neuroimaging parameters (Siever & Davis, 2004). Three neuroimaging studies aimed to examine the relationship between subclinical psychotic phenotypes and neurobiology. Surface and volume-based morphometric (VBM) methods were implemented to examine the variety of cortical and subcortical signatures of different phenotype dimensions. Study 1 investigated whether cortical surface gyrification -a maker of genetic and developmental influences on cortical morphology (Docherty et al., 2015; Haukvik et al., 2012)- is associated with dimensional psychosis prone phenomena (Konings, Bak, Hanssen, van Os, & Krabbendam, 2006; Stefanis et al., 2002). Early cortical organisation contributes to cognitive capacities in later life (Gautam et al., 2015; Gregory et al., 2016; Papini et al., 2020). Given that cognitive deficits are present in psychosis prone and clinical samples to varying extents (Hou et al., 2016; Siddi et al., 2017), Study 1 also explored the mediating role of cognition (both as a general measure and intelligence quotient) as a psychosis endophenotype in the relationship between regional gyrification and PLE distress. Study 2 and Study 3 used VBM to investigate structural brain correlates for psychotic-like experiences (PLE) and trait psychosis phenotypes (schizotypy). Different PLE facets (quantity and distress severity) (Hanssen, Bak, et al., 2005; Ising et al., 2012) were used to estimate whole-brain grey matter volume, followed by interaction models in subsequent prefrontal regions of interest (Study 2). The medial temporal lobe includes the hippocampal subfields, which are regions of interest in psychosis pathophysiology (Lieberman et al., 2018; Mathew et al., 2014; Schobel et al., 2013). Based on a previous study in schizoytypy (Sahakyan et al., 2020), Study 3 examined the relationship between schizotypal trait dimensions (Mason et al., 1995) and PLE, and their interactions, and hippocampal subfields and the amygdala. The results of Study 1 showed that psychometrically assessed PLE were associated with reduced gyrification in parietal and temporal regions, indicating that psychosis proneness correlates with neurodevelopmental factors (Fonville et al., 2019; Liu et al., 2016). A lack of mediating pathways between regional gyrification and PLE suggested that cognition effects may emerge in larger samples (Mollon et al., 2016) and/or increasingly psychosis pone phenotypes. Elaborating on the distinction between PLE quantity versus distress, Study 2 showed that PLE load, but not distress severity, were associated with volume increases in prefrontal and occipitotemporal regions. At increased distress severity for perceptual abnormalities, PLE were associated with regional volume reductions of the superior frontal gyrus. Study 3 showed differential relationships between schizotypy dimensions and volumes of the MTL that are involved in the pathophysiology of schizophrenia. PLE per se did not associate with amygdala or hippocampal subfield volumes, but a positive association between the hippocampal subiculum and PLE was moderated by positive schizotypy. Study 3 underscored the enhanced usefulness of schizotypy as an endophenotype in psychosis research when its multidimensional organisation (Grant, 2015; Vollema & van den Bosch, 1995) is respected. The results support the use of psychosis symptom dimensions, showing different (positive and negative) neuroanatomical associations. While case-control studies in schizophrenia show consistent volume reductions of the prefrontal and temporal cortices (Haijma et al., 2013; Honea, Crow, Passingham, & Mackay, 2005), these findings contribute to more heterogeneous volumetric relationships in nonclinical individuals. Reduced regional cortical gyrification proposes a continuous distribution of neurodevelopmental impacts. Distress severity and schizotypy occasioned modulatory effects in prefrontal and hippocampal subfield volumes, respectively. Collectively, these three cross-sectional studies extend previous research suggesting that dimensional phenotypes show neuroanatomical variation supportive of a psychosis continuum possibly characterised by an underlying non-linearity (Bartholomeusz et al., 2017; Binbay et al., 2012; Johns & van Os, 2001)

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

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

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

Abstract 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

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

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

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

Abstract 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

Brain structural network connectivity of formal thought disorder dimensions in affective and psychotic disorders

BACKGROUND: The psychopathological syndrome of formal thought disorder (FTD) is present in schizophrenia (SZ) but is also highly prevalent in major depression (MDD) and bipolar disorder (BD). 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 SAPS and SANS, we performed exploratory and confirmatory factor analyses in N=864 patients with MDD (n=689), BD (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 sub-dimensions and global structural connectome measures, we employed linear regression models. We used network-based statistic (NBS) 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. NBS identified subnetworks associated with FTD dimensions "disorganization" and "emptiness" but not with "incoherence". Post-hoc analyses on subnetworks did not reveal diagnosis x 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 MDD, BD and SZ associated with FTD dimensions that comprise predominantly brain regions implicated in speech. Results open an avenue for transdiagnostic, psychopathology informed, dimensional studies in pathogenetic research