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Coordinated Cortical Thickness Alterations across Psychiatric Conditions: A Transdiagnostic ENIGMA Study

Introduction: Mental disorders are increasingly conceptualized as overlapping spectra with underlying polygenicity, neurodevelopmental etiology, and clinical comorbidity. They share multi-level neurobiological alterations, including network-like brain structural alterations. However, whether alteration patterns covary across mental disorders in a biologically meaningful way is currently unknown. Methods: We accessed summary statistics on cortical thickness alterations from 12,024 patients with six mental disorders and 18,969 controls from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. First, we studied cortical thickness co-alteration networks as a form of pathological structural covariance. We identified regions exhibiting high inter-regional covariance across disorders ("hubs"), and regions that strongly connect to these hubs facilitating network spreading of disease effects ("epicenters"). Next, we applied manifold learning to reveal organizational gradients guiding transdiagnostic patterns of illness effects. Last, we tested whether these gradients capture differential cortical susceptibility with respect to normative cortical thickness covariance, cytoarchitectonic, transcriptomic, and meta-analytical task-based profiles. Results: Co-alteration network hubs were linked to normative connectome hubs and anchored to prefrontal and temporal disease epicenters. The principal gradient derived from manifold learning captured maximally different embedding of prefrontal and temporal epicenters within co-alteration networks, followed a normative cortical thickness gradient, and established a transcriptomic link to cortico-cerebello-thalamic circuits. Moreover, gradients segregated functional networks involved in basic sensory, attentional/perceptual, and domain-general cognitive processes, and distinguished between regional cytoarchitectonic profiles. Conclusion: Together, our findings indicate that disease impact occurs in a synchronized fashion and along multiple levels of hierarchical cortical organization. Such axes can help to disentangle the different neurobiological pathways underlying mental illness.