Altered Sensorimotor-to-Transmodal Hierarchical Organization in Schizophrenia

Abstract

For decades, schizophrenia has been primarily conceptualized as a disorder of high-order cognitive functions with deficits in executive brain regions. Yet due to the increasing reports of early sensory processing deficit, recent models focus more on the developmental effects of impaired sensory process on high-order functions. The present study examined whether this pathological interaction relates to an overarching system-level imbalance, specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. We applied a novel combination of connectome gradient and stepwise connectivity analysis to resting-state functional magnetic resonance imaging (rsfMRI) to characterize the sensorimotor-to-transmodal cortical hierarchy organization (96 patients vs. 122 controls). Using these techniques, we demonstrated compression of the cortical hierarchy organization in schizophrenia, with a prominent compression from the sensorimotor region and a less prominent compression from the frontal-parietal region, resulting in a diminished separation between sensory and fronto-parietal cognitive systems. Further analyses suggested reduced differentiation related to atypical functional connectome transition from unimodal to transmodal brain areas. Specifically, we found hypo-connectivity within unimodal regions and hyper-connectivity between unimodal regions and frontoparietal and ventral attention regions along the classical sensation-to-cognition continuum established in prior neuroanatomical work. The compression of cortical hierarchy organization represents a novel and integrative system-level substrate underlying the pathological interaction of early sensory and cognitive function in schizophrenia. This abnormal cortical hierarchy organization suggests cascaded impairments stemming from the disrupted somatosensory-motor system and inefficient integration of bottom-up sensory information with attentional demands and executive control processes partially account for high-level cognitive deficits characteristic of schizophrenia.

Macroscale Thalamic Functional Organization Disturbances and Underlying Core Cytoarchitecture in Early-Onset Schizophrenia

“…expansion might further result in disturbed cortical differentiation of unimodal and transmodal regions in EOS. A compression of the unimodal-to-transmodal cortical hierarchy was recently found in chronic adult-onset schizophrenia(51), contrasting with our observation of cortical-thalamic hierarchy expansion. Given age-dependent shifts in the macroscale cortical hierarchy(52), this inconsistence might due to their disparate stage of the illness and age of onset, or their usage of antipsychotic drugs.Further longitudinal works are needed to chart functional organization abnormalities of the thalamus and the cerebral cortex during the course of schizophrenia.…”

“…A cortical hierarchy dissociating sensory from transmodal regions has been implicated in cognitive processing, describing a functional processing axis from perceptual/action towards abstract cognition functions including social cognition and memory (Margulies et al, 2016; Mesulam, 1998). At the same time, a compression of the unimodal-to-transmodal cortical hierarchy was recently found in chronic adult-onset schizophrenia (Debo Dong et al, 2020), in contrast with our findings of expansion. Given age-dependent shifts in the macroscale cortical hierarchy (Dong, Margulies, Zuo, & Holmes, 2021), this inconsistence might due to their disparate stage of the illness and age of onset, or their usage of antipsychotic drugs.…”

Reproducible abnormalities of functional gradient reliably predict clinical and cognitive symptoms in schizophrenia

“…Meanwhile, a number of previous rs-fMRI studies have also discovered abnormal functional connectivity involving most of these regions (Mitchell et al 2001;Karbasforoushan and Woodward 2012). However, our identified abnormal brain regions were not fully consistent with a recent gradient study on SZ (Dong et al 2020 Mar 8). This inconsistent might be ascribed to differences in sample size (Button To investigate associations between abnormal gradients and clinical symptoms in SZ, we performed regression analyses using generalized additive models (GAMs) (Hastie and Tibshirani 1986;Hastie and Tibshirani 1995 (Torrey 2007).…”

Latent clinical-anatomical dimensions of schizophrenia

“…This raises the possibility that multiple pathological processes, originating from opposing ends of the putative sensory-fugal hierarchy, may be involved in the disease. Interestingly, two recent functional imaging studies found evidence of atypical functional connectivity and integration between unimodal and transmodal cortices 96,97 . Our results show that these deficits in functional coordination may ultimately originate from underlying anatomical abnormalities, reflecting large-scale molecular and cellular gradients.…”