Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

Abstract

Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11. 2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.Introduction 1 A number of rare genetic variants occurring through the deletion or duplication of 2 chromosomal segments are associated with significantly increased risk for a range of 3 neurodevelopmental disorders (ND), including schizophrenia, autism spectrum disorder 4 (ASD), and developmental delay 1 . Although the underlying mechanisms remain poorly 5 understood, these copy number variants (referred to hereafter as ND-CNVs) are thought to 6 increase the risk for psychopathology through alterations in neural structure and function. Thus, 7 neuroimaging studies in participants with ND-CNVs provide a unique opportunity to study 8 intermediate phenotypes of mental disorders. 9Furthermore, recent work suggests that CNV-specific phenotypic outcomes are limited, 10 pointing instead to a large degree of similarity across phenotypes associated with different ND-11 CNVs 2,3 . Focusing on convergent neural alterations across different genotypes can thus help 12 elucidate the mechanisms linking ND-CNVs at different loci to a shared psychopathology and 13 increase in neurodevelopmental risk. 14 Failures of functional neural integration have long been considered a hallmark of 15 neurodevelopmental disorders such as schizophrenia 4,5 . In recent years, evidence of disrupted 16 connectivity has also emerged in ASD populations 6,7 and has been shown to transcend 17 diagnostic boundaries 8 . ND-CNVs are thought to increase disorder risk by acting on large-scale 18 neural integration through molecular and cellular mechanisms 9 . Studying functional network 19 alterations in participants with ND-CNVs could thus help establish their rel...

Alterations in resting-state activity and functional connectivity in children with 22q11.2 deletion syndrome

“…Despite the proposed neuronal integration deficits in 22q11.2DS and other neurodevelopmental CNVs, there have been relatively few studies of cortical oscillations in these high-risk groups. In a recent resting- state MEG study in adult CNV carriers, we found common patterns of oscillatory dysconnectivity across nine different neurodevelopmental CNV loci, including 22q11.2DS, suggesting a putative mechanism by which neurodevelopmental CNVs could increase risk of psychopathology (41). Due to the relatively small numbers of participants with each CNV, it was not possible to explore the associations between oscillatory activity and neurodevelopmental symptoms or psychopathology.…”

“…The functional connectivity changes we found in children are similar to those previously reported by our research group in adult neurodevelopmental CNV carriers. (41). While there were relatively few participants with 22q11.2DS in that study (n=14), analysis of the 22q11.2 group alone found similar connectivity reductions as the cross-CNV analysis but in addition, a number of nodes with hyperconnectivity were identified.…”

Measuring robust functional connectivity from resting-state MEG using amplitude and entropy correlation across frequency bands and temporal scales

“…While it is interesting that MRVE correlation has shown promise as a measure of functional connectivity, the true test of its usefulness will be its performance in patient groups. Neural variability measures such as Multi-scale Entropy (MSE) ( Bosl, Tierney, Tager-flusberg, Nelson, 2011 , Costa, Goldberger, Peng, 2005 , Ghanbari, Bloy, Edgar, Blaskey, Verma, Roberts, 2015 , Mizuno, Takahashi, Cho, Kikuchi, Murata, Takahashi, Wada, 2010 ), and AEC connectivity ( Andreou, Nolte, Leicht, Polomac, Hanganu-opatz, Lambert, Engel, Mulert, 2015 , Dima, Adams, Linden, Baird, Smith, Foley, Perry, Routley, Magazzini, Drakesmith, Williams, Doherty, van den Bree, Owen, Hall, Linden, Singh, 2020 , Koelewijn, Hamandi, Brindley, Brookes, Routley, Muthukumaraswamy, Williams, Thomas, Kirby, te Water Naudé, Gibbon, Singh, 2015 , Koelewijn, Lancaster, Linden, Dima, Bethany, Magazzini, Barawi, Brindley, Adams, Tansey, Bompas, Tales, Bayer, Singh, 2019 ) have both been shown to be able to distinguish patient groups from controls. Future work will investigate whether MRVE correlation can provide understanding about connectivity changes associated with disease, in comparison to conventional measures based on the oscillatory components of brain function.…”

Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes

“…Studies have also explored similarities in functional connectivity patterns across CNVs. A magnetoencephalography study investigated resting-state oscillatory connectivity and reported decreased connectivity between occipital, temporal, and parietal areas in CNV carriers (64). Moreau et al (65) combined functional MRI data from 16p11.2 and 22q11.2 CNV carriers; individuals with idiopathic ASD, schizophrenia, and attention-deficit/hyperactivity disorder; and respective control subjects to look for convergent patterns of functional connectivity alterations.…”