Schizophrenia Polygenic Risk During Typical Development Reflects Multiscale Cortical Organization

Kirschner, Matthias; Paquola, Casey; Khundrakpam, Budhachandra; Vainik, Uku; Bhutani, Neha; Hodzic-Santor, Benazir; Georgiadis, Foivos; Al‐Sharif, Noor; Mišić, Bratislav; Bernhardt, Boris C.; Evans, Alan C.

doi:10.1016/j.bpsgos.2022.08.003

Cited by 7 publications

(7 citation statements)

References 86 publications

(124 reference statements)

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“…According to our network models, epicenters emerging early in the disease process might be further characterized by distinct alterations in genetic activity, macro- or micromorphology and/or activity. Aberrant signaling of cortical development involving myelination, branching, and synaptic pruning (34, 66, 67) might propagate from focal epicenters to connected regions in a network-spreading pattern leading to the characteristic pattern of cortical alteration. Applying multi-omic approaches longitudinally across neurodevelopment and early SCZ stages are of interest to test this hypothesis and examine the role of the derived epicenters in aberrant developmental processes.…”

Section: Discussionmentioning

confidence: 99%

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Georgiadis

Larivière

Glahn

et al. 2023

Preprint

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Objective: Schizophrenia is associated with widespread brain-morphological alterations, believed to be shaped by the underlying connectome architecture. This study tests whether large-scale structural reorganization in schizophrenia relates to normative network architecture, in particular regional centrality/hubness and connectivity patterns. We examine network effects in schizophrenia across different disease stages, and transdiagnostically explore consistency of such relationships in patients with bipolar and major depressive disorder. Methods: We studied anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites. Case-control patterns of structural alterations were evaluated against two network susceptibility models: 1) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; 2) epicenter models, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alteration patterns. Both susceptibility models were tested across schizophrenia disease stages and compared to meta-analytic bipolar and major depressive disorder case-control maps. Results: In schizophrenia, regional gray matter reductions co-localized with interconnected hubs, in both the functional (r=0.58, pspin<0.0001) and structural connectome (r=0.32, pspin=0.01). Epicenters were identified in temporo-paralimbic regions, extending to frontal areas. We found unique epicenters for first-episode and early stages, and a shift from occipital to temporal-frontal epicenters in chronic stages. Transdiagnostic comparisons revealed shared epicenters in schizophrenia and bipolar, but not major depressive disorders. Conclusions: Cortical reorganization over the course of schizophrenia closely reflects brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters. The observed overlapping epicenters for schizophrenia and bipolar disorder furthermore suggest shared pathophysiological processes within the schizophrenia-bipolar-spectrum.

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Section: Discussionmentioning

confidence: 99%

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Georgiadis

Larivière

Glahn

et al. 2023

Preprint

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“…The coordinated processes of cortical maturation during childhood and adolescence not only reflect typical development but also highlight potential vulnerabilities to neurodevelopmental conditions 35,70,71 . Comparing the CT profiles of neurodevelopmental conditions with those of both schizotypy dimensions, we observed overlapping associations of both schizotypy dimensions and ADHD.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, brain-wide cortical thickness patterns in schizotypy 31 were significantly associated with patterns of cortical thinning observed in schizophrenia 32 , suggesting a neurobiological continuum within the extended psychosis phenotype. Parallel research has expanded this perspective, showing that genetic risk, clinical high-risk and neuropsychiatric conditions, including schizophrenia, exhibit spatial similarity of cortical alterations [33][34][35] . These shared patterns may be driven by a complex interplay of molecular and connectomic vulnerabilities 36 as well as neurotransmitter profiles 37 , which manifest as coordinated alterations in cortical thickness 38,39 .…”

Section: Introductionmentioning

confidence: 99%

Multiscale characterization of cortical signatures in positive and negative schizotypy: A worldwide ENIGMA study

Kirschner,

Hodzic-Santor,

Kennedy

et al. 2024

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Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2,730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them to disorder-specific, micro-architectural, connectome, and neurotransmitter-level measures. Positive and negative schizotypy were associated with thinner frontal and thicker paralimbic cortical areas, respectively, and were differentially linked to cortical patterns of schizophrenia-spectrum and neurodevelopmental conditions. Furthermore, these schizotypal cortical patterns mapped onto local attributes of gene expression, cortical myelination, D1 and histamine receptor distributions. Network models identified cortical hub vulnerability to schizotypy-related thickness reduction and epicenters in sensorimotor-to-association and paralimbic areas. This study yields insights into the complex cortical signatures of schizotypy and their relationship to diverse features of cortical organization.

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“…Conversely, increased cortical thickness in TD children appears to reflect higher polygenic risk for schizophrenia (55). Excessive thickening of the cortex has been found in healthy individuals with increased schizotypy scores which is thought to be an abnormal neurodevelopmental trait (56).…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmentally rooted epicenters in schizophrenia: sensorimotor-association spatial axis of cortical thickness alterations

Fan,

Xu,

Hettwer

et al. 2024

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Pathologic perturbations in schizophrenia have been suggested to propagate via the functional and structural connectome across the lifespan. Yet how the connectome guides early cortical reorganization of developing schizophrenia remains unknown. Here, we used early-onset schizophrenia (EOS) as a neurodevelopmental disease model to investigate putative early pathologic origins that propagate through the functional and structural connectome. We compared 95 patients with antipsychotic-naïve first-episode EOS and 99 typically developing controls (7–17 years of age, 120 females). Whereas patients showed widespread cortical thickness reductions, thickness increases were observed in primary cortical areas. Using normative connectomics models, we found that epicenters of thickness reductions were situated in association regions linked to language, affective, and cognitive functions, while epicenters of increased thickness in EOS were located in sensorimotor regions subserving visual, somatosensory, and motor functions. Using post-mortem transcriptomic data of six donors, we observed that the epicenter map differentiated oligodendrocyte-related transcriptional changes at its sensory apex and the association end was related to expression of excitatory/inhibitory neurons. More generally, we observed that the epicenter map was associated with neurodevelopmental disease gene dysregulation and human accelerated region genes, suggesting potential shared genetic determinants across various neurodevelopmental disorders. Taken together, our results underscore the developmentally rooted pathologic origins of schizophrenia and their transcriptomic overlap with other neurodevelopmental diseases.

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Schizophrenia Polygenic Risk During Typical Development Reflects Multiscale Cortical Organization

Cited by 7 publications

References 86 publications

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study

Multiscale characterization of cortical signatures in positive and negative schizotypy: A worldwide ENIGMA study

Neurodevelopmentally rooted epicenters in schizophrenia: sensorimotor-association spatial axis of cortical thickness alterations

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