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)

Investigation of dimensional phenomenology and neurobiology across affective and psychotic disorders

For a long time, traditional classification systems have been used to categorize mental disorders into strict classes based on a set of specific and standardized criteria. Such classifications assume a clear cut off between disorders. However, research using these classification systems fail to identify transdiagnostic markers and “points of rarity” separating mental disorders. Categorical approaches are limited by the large neurobiological overlapping of phenomenology as well as molecular genetics, neuro-anatomy and function, and environmental risk across disorders. Moreover, categorical approaches merely consider characteristics above and below the given categorical thresholds using not otherwise specified diagnoses, not fitting to other officially specified categories. Given the limitations of categorical approaches, dimensional factor models can be used as a valuable framework providing significant progress for the understanding of the neurobiology of the major psychiatric disorders (major depressive disorder, bipolar disorder, schizophrenia spectrum disorder). Previous studies show a range of different factor models, indicating that descriptive psychopathology might be organized in a bifactorial or hierarchical framework. However, there is still a lack of comprehensive factorial models comprising a broad range of symptoms across the major psychiatric disorders. Moreover, the neuro-anatomical and neuro-cognitive correlates of transdiagnostic psychopathological factors remain largely elusive. Categorical studies on overlapping gray matter volume alterations across disorders compared to a healthy control group show paralimbic and heteromodal regions to be commonly altered across disorders. In addition, the transdiagnostic investigation of neuro-cognitive measures shows large overlaps and comparable results across disorders and domains with motor speed being the only domain separating disorders. To overcome the reported obstacles, the studies underlying this dissertation investigate the factorial structure of a broad range of psychopathological symptoms across affective and psychotic disorders. Further, dimensional factors are used to determine the underlying neuro-anatomical and neuro-cognitive correlates of descriptive psychopathology. STUDY I demonstrates a cross-validated factor model comprising five first order and two second order factors, supporting the use of hierarchical models. The extracted first order factors (depression, negative syndrome, positive formal thought disorder, paranoid-hallucinatory syndrome, increased appetite) are present in all diagnostic categories, suggesting a diagnosis-shared phenomenology. STUDY II examines the brain structural correlates of the factors derived from STUDY I. Results include a negative association of the negative syndrome with the bilateral frontal opercula. Positive formal thought disorder is negatively associated with the right middle frontal gyrus and with the left amygdala-hippocampus-complex. The paranoid-hallucinatory syndrome is negatively associated with two whole brain clusters (right fusiform gyrus and left middle frontal gyrus) as well as regions-of-interest including the left angular gyrus, bilateral thalami, left postcentral gyrus and left posterior cingulate gyrus. Investigating the neuro-cognitive correlates of psychopathological factors, STUDY III indicates state of illness-dependent associations in almost all cognitive domains. While positive formal thought disorder and the negative syndrome show most pronounced correlations, no or only weak correlations emerge for the other factors. Finally, STUDY IV investigates formal thought disorder in more detail. Results indicate a three factor model (verbosity, emptiness, disorganization) that is differentially associated with gray and white matter brain structure. The verbosity factor is negatively associated with gray matter volume of the temporo-occipital language junction and positively with the white matter microstructure of the inferior longitudinal fascicle and the posterior part of the cingulum bundle. Emptiness is negatively associated with the gray matter volume of the left hippocampus and thalamus but not with white matter. The disorganization factor associates with the white matter structure of the bilateral anterior thalamic radiation and with the hippocampal part of the right cingulum bundle. In conclusion, this dissertation can be interpreted as a first effort overcoming the limitations given by previous categorical approaches. The psychopathological factor models reported are linked to brain structural and neuro-cognitive measures, supporting the view of diagnosis shared and independent biological mechanisms. The studies of this dissertation open up completely new approaches for pathogenic and etiological research. Dimensional methods as applied in this dissertation constitute the basis for a new taxonomy that can in a next step be used to improve prediction, treatment and therapy of the major psychiatric disorders

Morphogenetic Principles of Brain Organisation in Health and Disease

Non-invasive neuroimaging methods, such as MRI, provide a window into the structure of the mammalian brain. However, despite the ubiquity of these methods, the biological interpretation of the information obtained using these tools remains elusive. In order to accurately link this macroscale data to microscale measurements, it is critical that the construct validity is high. This thesis provides novel analyses, pipelines and methods to: i) generate and validate maps of brain organisation obtained via MRI, and ii) demonstrate the utility of these methods in capturing elements of cognition and psychopathology. First, in Chapter 1, I review some of the neuroscientific context for the new methods presented, from cytoarchitecture to gene expression to connectomes. Chapters 2-4 introduce a new method, “Morphometric Similarity Mapping”, which captures the brain organisation of an individual by mapping the relationships of multiple features of the cerebral cortex. Chapter 2 focuses on the development of the analysis pipeline and the graph theoretical features of the resulting morphometric similarity networks (MSNs), with an emphasis on reproducibility. Chapter 3 highlights the generalisability of MSNs to the macaque monkey, linking MSNs to ex vivo tract tracing experiments and presenting new tools for processing non-human imaging data; as well as evidence that MSN topography is organised by cytoarchitectonic features. Chapter 4 is focused on determining the transcriptomic correlates of MSNs using publicly available gene expression maps, and on applying MSNs to examine the relationship between brain organisation and intelligence. Chapter 5 is dedicated to rigorous evaluation of the applicability of MSNs to measure specific disease-relevant phenotypes in 8 rare genetic disorder cohorts. This includes the validation of novel methods for utilising data from both single-cell sequencing technologies and differential gene expression experiments (in multiple tissue types) in analysing neuroimaging and bulk transcriptomic brain maps. Chapter 6 provides a brief summary and presents some ongoing and future projects expanding on this original work. It also importantly discusses a general framework of comparing brain maps, including MSNs and gene expression, as well as other canonical maps of brain structure and function. Altogether, this thesis presents and evaluates novel methods and applications for integrating multimodal neuroimaging data with genetic data derived from multiple tissue types and through various acquisition strategies. It also includes tools for performing these analyses in non-human primates, and pipelines for statistically comparing brain maps. These results not only provide insight into the manifestation of brain-related changes due to various components of human variation, but also provides a framework for evaluating this variation at multiple biological scales purely from non-invasive neuroimaging data

Identification of neurobiological mechanisms associated with attention deficits in adults post traumatic brain injury

Traumatic Brain Injury (TBI) is one of the major public health concerns with approximately 70 million new cases occurring worldwide per year. It is often caused by a forceful bump, blow, or jolt to the head, resulting in brain tissue damage and normal brain functions disruption. All grades of TBI, ranging from mild to severe, can cause wide-ranging and long-term effects on affected individuals, resulting in physical impairments, and neurocognitive consequences that permanently affect their abilities to perform daily activities. Attention deficits are the most common persisting neurocognitive consequences following TBI, which significantly contribute to poor academic and social functioning, and life-long learning difficulties of affected individuals. However, attention deficits have been evaluated and treated based on symptom endorsements from subjective observations, with few therapeutic interventions successfully translated to the clinic. The consensus regarding appropriate evaluation and treatment of TBI induced attention deficits in this cohort is rather limited due to the lack of investigations of the neurobiological substrates associated with this syndrome. The overall aim of this dissertation research is to systematically investigate the neurobiological mechanisms associated with attention deficits in adults post TBI by utilizing multiple powerful neuroimaging techniques including the functional near-infrared spectroscopy (fNIRS) and multimodal magnetic resonance imaging (MRI), with an ultimate goal of translating hypothesis-driven neurobiological correlates into the quantitatively measurable biomarkers for diagnosis of TBI-induced attention deficits and development of more refined long-term treatment and intervention strategies. This dissertation research is conducted through three specific projects. Project 1 focuses on the investigation of brain functional patterns including the regional cortical brain activation and between-regional pairwise functional connectivity responding to visual sustained attention processing in individuals with and without TBI, by utilizing the fNIRS technique. Project 2 continues the examination of brain functional patterns by assessing the whole brain network topological properties responding to visual sustained attention processing in a larger sample of individuals with and without TBI, by utilizing the functional MRI technique and a graph theoretic approach. Project 3, on the other hand, investigates the brain structural characteristics based on the same sample involved in Project 2, by utilizing the structural MRI and diffusion tensor imaging techniques. For all these three projects, the differences of these brain imaging measures are compared between the groups of TBI and control. Correlation analyses are further conducted between those brain imaging measures which shows significant between-group differences and attention-related behaviors. In addition, Project 3 additionally investigates gender-specific patterns of the altered brain structural properties in TBI patients, relative to controls. The outcome of this novel and valuable dissertation research may shed light on the neural mechanisms of attention deficits in adults post TBI, and may suggest the neurobiological targets for treatment of this severe and common condition. It may also provide important neural foundation for future research to develop effective rehabilitation strategies to improve attention processing in adults post TBI

The Examination of White Matter Microstructure, Autism Traits, and Social Cognitive Abilities in Neurotypical Adults

The purpose of this study was to examine the relationships among mentalizing abilities, self-reported autism traits, and two white matter tracts, uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF), in neurotypical adults. UF and ILF were hypothesized to connect brain regions implicated in a neuroanatomical model of mentalizing. Data were available for 24 neurotypical adults (mean age = 21.92 (4.72) years; 15 women). Tract-based spatial statistics (TBSS) was used to conduct voxelwise cross-participant comparisons of fractional anisotropy (FA) values in UF and ILF as predicted by mentalizing abilities and self-reported autism traits. Self-reported autism traits were positively related to FA values in left ILF. Results suggest that microstructural differences in left ILF are specifically involved in the expression of subclinical autism traits in neurotypical individuals

Neuroanatomical correlates of cognitive dysfunction in obstructive sleep apnoea

Obstructive sleep apnoea (OSA) has been reported to be associated with brain hypotrophy and cognitive dysfunction; however, whether these normalise after treatment is unclear. The overall aim of this thesis is to investigate the relationship between OSA and brain structure using FreeSurfer (a new automated technique that reliably measures brain structures). I have investigated changes in brain morphology and the newly described phenomenon in OSA of ischaemic preconditioning. Chapters 4 and 5 will also assess brain structural response to CPAP, and investigate the association between brain structure and cognitive function in OSA. Chapter 3 reports an observational study investigating brain structure. FreeSurfer analysis of magnetic resonance imaging (MRI) found OSA patients had hypertrophy in the right hippocampus (p=0.03) and right choroid plexus (p=0.02) but hypotrophy of the corpus callosum (p=0.04) compared to healthy controls. Chapter 4 reports a randomised controlled trial of CPAP in OSA. At baseline hypotrophy was seen in the corpus callosum (p=0.03) and pallidum (p=0.03) of OSA patients compared to healthy controls. Hypertrophic changes in the right thalamus were seen in the CPAP group after 1 month (p=0.06), associated with improvement in verbal memory (p=0.04). Chapter 5 reports a randomised controlled trial of CPAP in older patients with OSA. A significant decrease in left fimbria volume was seen in the CPAP group (p=0.01). A significant increase in the left presubiculum volume was seen in the best supportive care group (p=0.03). No hippocampal hypertrophy was seen in the CPAP group. In summary, young and middle-aged OSA patients had evidence of brain hypotrophy, but also areas of hypertrophy that may signify dendritic sprouting and increased connectivity as a result of ischaemic preconditioning. This allows recovery of brain hypotrophy after CPAP treatment. This was not seen in older OSA patients suggesting an age-related difference which may have implications for OSA treatment in older people.Open Acces

Predictive cognition in dementia: the case of music

The clinical complexity and pathological diversity of neurodegenerative diseases impose immense challenges for diagnosis and the design of rational interventions. To address these challenges, there is a need to identify new paradigms and biomarkers that capture shared pathophysiological processes and can be applied across a range of diseases. One core paradigm of brain function is predictive coding: the processes by which the brain establishes predictions and uses them to minimise prediction errors represented as the difference between predictions and actual sensory inputs. The processes involved in processing unexpected events and responding appropriately are vulnerable in common dementias but difficult to characterise. In my PhD work, I have exploited key properties of music – its universality, ecological relevance and structural regularity – to model and assess predictive cognition in patients representing major syndromes of frontotemporal dementia – non-fluent variant PPA (nfvPPA), semantic-variant PPA (svPPA) and behavioural-variant FTD (bvFTD) - and Alzheimer’s disease relative to healthy older individuals. In my first experiment, I presented patients with well-known melodies containing no deviants or one of three types of deviant - acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). I assessed accuracy detecting melodic deviants and simultaneously-recorded pupillary responses to these deviants. I used voxel-based morphometry to define neuroanatomical substrates for the behavioural and autonomic processing of these different types of deviants, and identified a posterior temporo-parietal network for detection of basic acoustic deviants and a more anterior fronto-temporo-striatal network for detection of syntactic pitch deviants. In my second chapter, I investigated the ability of patients to track the statistical structure of the same musical stimuli, using a computational model of the information dynamics of music to calculate the information-content of deviants (unexpectedness) and entropy of melodies (uncertainty). I related these information-theoretic metrics to performance for detection of deviants and to ‘evoked’ and ‘integrative’ pupil reactivity to deviants and melodies respectively and found neuroanatomical correlates in bilateral dorsal and ventral striatum, hippocampus, superior temporal gyri, right temporal pole and left inferior frontal gyrus. Together, chapters 3 and 4 revealed new hypotheses about the way FTD and AD pathologies disrupt the integration of predictive errors with predictions: a retained ability of AD patients to detect deviants at all levels of the hierarchy with a preserved autonomic sensitivity to information-theoretic properties of musical stimuli; a generalized impairment of surprise detection and statistical tracking of musical information at both a cognitive and autonomic levels for svPPA patients underlying a diminished precision of predictions; the exact mirror profile of svPPA patients in nfvPPA patients with an abnormally high rate of false-alarms with up-regulated pupillary reactivity to deviants, interpreted as over-precise or inflexible predictions accompanied with normal cognitive and autonomic probabilistic tracking of information; an impaired behavioural and autonomic reactivity to unexpected events with a retained reactivity to environmental uncertainty in bvFTD patients. Chapters 5 and 6 assessed the status of reward prediction error processing and updating via actions in bvFTD. I created pleasant and aversive musical stimuli by manipulating chord progressions and used a classic reinforcement-learning paradigm which asked participants to choose the visual cue with the highest probability of obtaining a musical ‘reward’. bvFTD patients showed reduced sensitivity to the consequence of an action and lower learning rate in response to aversive stimuli compared to reward. These results correlated with neuroanatomical substrates in ventral and dorsal attention networks, dorsal striatum, parahippocampal gyrus and temporo-parietal junction. Deficits were governed by the level of environmental uncertainty with normal learning dynamics in a structured and binarized environment but exacerbated deficits in noisier environments. Impaired choice accuracy in noisy environments correlated with measures of ritualistic and compulsive behavioural changes and abnormally reduced learning dynamics correlated with behavioural changes related to empathy and theory-of-mind. Together, these experiments represent the most comprehensive attempt to date to define the way neurodegenerative pathologies disrupts the perceptual, behavioural and physiological encoding of unexpected events in predictive coding terms

Mapping genome-wide neuropsychiatric mutation effects on functional brain connectivity : c opy number variants delineate dimensions contributing to autism and schizophrenia

Les recherches menées pour comprendre les troubles du spectre autistique (TSA) et la schizophrénie (SZ) ont communément utilisé une approche dite descendante, partant du diagnostic clinique pour investiguer des phénotypes intermédiaires cérébraux ainsi que des variations génétiques associées. Des études transdiagnostiques récentes ont remis en question ces frontières nosologiques, et suggèrent des mécanismes étiologiques imbriqués. L’approche montante propose de composer des groupes de porteurs d’un même variant génétique afin d’investiguer leur contribution aux conditions neuropsychiatriques (NPs) associées. Les variations du nombre de copies (CNV, perte ou gain d’un fragment d’ADN) figurent parmi les facteurs biologiques les plus associés aux NPs, et sont dès lors des candidats particulièrement appropriés. Les CNVs induisant un risque pour des conditions similaires, nous posons l’hypothèse que des classes entières de CNVs convergent sur des dimensions d’altérations cérébrales qui contribuent aux NPs. L’imagerie fonctionnelle au repos (rs-fMRI) s’est révélée un outil prometteur en psychiatrie, mais presqu’aucune étude n’a été menée pour comprendre l’impact des CNVs sur la connectivité fonctionnelle cérébrale (FC). Nos objectifs étaient de: 1) Caractériser l’effet des CNVs sur la FC; 2) Rechercher la présence des motifs conférés par ces signatures biologiques dans des conditions idiopathiques; 3) Tester si la suppression de gènes intolérants à l’haploinsuffisance réorganise la FC de manière indépendante à leur localisation dans le génome. Nous avons agrégé des données de rs-fMRI chez: 502 porteurs de 8 CNVs associées aux NPs (CNVs-NP), de 4 CNVs sans association établie, ainsi que de porteurs de CNVs-NPs éparses; 756 sujets ayant un diagnostic de TSA, de SZ, ou de trouble déficitaire de l’attention/hyperactivité (TDAH), et 5377 contrôles. Les analyses du connectome entier ont montré un effet de dosage génique positif pour les CNVs 22q11.2 et 1q21.1, et négatif pour le 16p11.2. La taille de l’effet des CNVs sur la FC était corrélée au niveau de risque psychiatrique conféré par le CNV. En accord avec leurs effets sur la cognition, l’effet des délétions sur la FC était plus élevé que celui des duplications. Nous avons identifié des similarités entre les motifs cérébraux conférés par les CNVs-NP, et l’architecture fonctionnelle des individus avec NPs. Le niveau de similarité était associé à la sévérité du CNV, et était plus fort avec la SZ et les TSA qu’avec les TDAH. La comparaison des motifs conférés par les délétions les plus sévères (16p11.2, 22q11.2) à l’échelle fonctionnelle, et d’expression génique, nous a confirmé l’existence présumée de relation entre les mutations elles-mêmes. À l’aide d’une mesure d’intolérance aux mutations (pLI), nous avons pu inclure tous les porteurs de CNVs disponibles, et ainsi identifier un profil d’haploinsuffisance impliquant le thalamus, le cortex antérieur cingulaire, et le réseau somato-moteur, associé à une diminution de mesure d’intelligence générale. Enfin, une analyse d’exploration factorielle nous a permis de confirmer la contribution de ces régions cérébrales à 3 composantes latentes partagées entre les CNVs et les NPs. Nos résultats ouvrent de nouvelles perspectives dans la compréhension des mécanismes polygéniques à l’oeuvre dans les maladies mentales, ainsi que des effets pléiotropiques des CNVs.Research on Autism Spectrum Disorder (ASD) and schizophrenia (SZ) has mainly adopted a ‘top-down’ approach, starting from psychiatric diagnosis, and moving to intermediate brain phenotypes and underlying genetic factors. Recent cross-disorder studies have raised questions about diagnostic boundaries and pleiotropic mechanisms. By contrast, the recruitment of groups based on the presence of a genetic risk factor allows for the investigation of molecular pathways related to a particular risk for neuropsychiatric conditions (NPs). Copy number variants (CNVs, loss or gain of a DNA segment), which confer high risk for NPs are natural candidates to conduct such bottom-up approaches. Because CNVs have a similar range of adverse effects on NPs, we hypothesized that entire classes of CNVs may converge upon shared connectivity dimensions contributing to mental illness. Resting-state functional MRI (rs-fMRI) studies have provided critical insight into the architecture of brain networks involved in NPs, but so far only a few studies have investigated networks modulated by CNVs. We aimed at 1) Delineating the effects of neuropsychiatric variants on functional connectivity (FC), 2) Investigating whether the alterations associated with CNVs are also found among idiopathic psychiatric populations, 3) Testing whether deletions reorganize FC along general dimensions, irrespective of their localization in the genome. We gathered rsfMRI data on 502 carriers of eight NP-CNVs (high-risk), four CNVs without prior association to NPs as well as carriers of eight scarcer NP-CNVs. We also analyzed 756 subjects with idiopathic ASD, SZ, and attention deficit hyperactivity disorder (ADHD), and 5,377 controls. Connectome-wide analyses showed a positive gene dosage effect for the 22q11.2 and 1q21.1 CNVs, and a negative association for the 16p11.2 CNV. The effect size of CNVs on relative FC (mean-connectivity adjusted) was correlated with the known level of NP-risk conferred by CNVs. Consistent with results on cognition, we also reported that deletions had a larger effect size on FC than duplications. We identified similarities between high-risk CNV profiles and the connectivity architecture of individuals with NPs. The level of similarity was associated with mutation severity and was strongest in SZ, followed by ASD, and ADHD. The similarity was driven by the thalamus, and the posterior cingulate cortex, previously identified as hubs in transdiagnostic psychiatric studies. These results raised questions about shared mechanisms across CNVs. By comparing deletions at the 16p11.2 and 22q11.2 loci, we identified similarities at the connectivity, and at the gene expression level. We extended this work by pooling all deletions available for analysis. We asked if connectivity alterations were associated with the severity of deletions scored using pLI, a measure of intolerance to haploinsufficiency. The haploinsufficiency profile involved the thalamus, anterior cingulate cortex, and somatomotor network and was correlated with lower general intelligence and higher autism severity scores in 3 unselected and disease cohorts. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and NPs. Our results open new avenues for understanding polygenicity in psychiatric conditions, and the pleiotropic effect of CNVs on cognition and on risk for neuropsychiatric disorders

Atypical measures of diffusion at the gray-white matter boundary in autism spectrum disorder in adulthood

Autism spectrum disorder (ASD) is a highly complex neurodevelopmental condition that is accompanied by neuroanatomical differences on the macroscopic and microscopic level. Findings from histological, genetic, and more recently in vivo neuroimaging studies converge in suggesting that neuroanatomical abnormalities, specifically around the gray-white matter (GWM) boundary, represent a crucial feature of ASD. However, no research has yet characterized the GWM boundary in ASD based on measures of diffusion. Here, we registered diffusion tensor imaging data to the structural T1-weighted images of 92 adults with ASD and 92 matched neurotypical controls in order to examine between-group differences and group-by-sex interactions in fractional anisotropy and mean diffusivity sampled at the GWM boundary, and at different sampling depths within the superficial white and into the gray matter. As hypothesized, we observed atypical diffusion at and around the GWM boundary in ASD, with between-group differences and group-by-sex interactions depending on tissue class and sampling depth. Furthermore, we identified that altered diffusion at the GWM boundary partially (i.e., ~50%) overlapped with atypical gray-white matter tissue contrast in ASD. Our study thus replicates and extends previous work highlighting the GWM boundary as a crucial target of neuropathology in ASD, and guides future work elucidating etiological mechanisms