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 fMRI to characterize the sensorimotor-to-transmodal cortical hierarchy organization (96 patients v. 122 controls).

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 fronto-parietal and ventral attention regions along the classical sensation-to-cognition continuum (voxel-level corrected, p < 0.05).

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 cascading impairments from the disruption of the 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.

Neuroimaging characteristics have demonstrated disrupted functional organization in schizophrenia (SZ), involving large-scale networks within grey matter (GM). However, previous studies have ignored the role of white matter (WM) in supporting brain function.

Using resting-state functional MRI and graph theoretical approaches, we investigated global topological disruptions of large-scale WM and GM networks in 93 SZ patients and 122 controls. Six global properties [clustering coefficient (Cp), shortest path length (Lp), local efficiency (Eloc), small-worldness (σ), hierarchy (β) and synchronization (S) and three nodal metrics [nodal degree (Knodal), nodal efficiency (Enodal) and nodal betweenness (Bnodal)] were utilized to quantify the topological organization in both WM and GM networks.

At the network level, both WM and GM networks exhibited reductions in Eloc, Cp and S in SZ. The SZ group showed reduced σ and β only for the WM network. Furthermore, the Cp, Eloc and S of the WM network were negatively correlated with negative symptoms in SZ. At the nodal level, the SZ showed nodal disturbances in the corpus callosum, optic radiation, posterior corona radiata and tempo-occipital WM tracts. For GM, the SZ manifested increased nodal centralities in frontoparietal regions and decreased nodal centralities in temporal regions.

These findings provide the first evidence for abnormal global topological properties in SZ from the perspective of a substantial whole brain, including GM and WM. Nodal centralities enhance GM areas, along with a reduction in adjacent WM, suggest that WM functional alterations may be compensated for adjacent GM impairments in SZ.

Previous studies in schizophrenia revealed abnormalities in the cortico-cerebellar-thalamo-cortical circuit (CCTCC) pathway, suggesting the necessity for defining thalamic subdivisions in understanding alterations of brain connectivity.

To parcellate the thalamus into several subdivisions using a data-driven method, and to evaluate the role of each subdivision in the alterations of CCTCC functional connectivity in patients with schizophrenia.

There were 54 patients with schizophrenia and 42 healthy controls included in this study. First, the thalamic structural and functional connections computed, based on diffusion magnetic resonance imaging (MRI, white matter tractography) and resting-state functional MRI, were clustered to parcellate thalamus. Next, functional connectivity of each thalamus subdivision was investigated, and the alterations in thalamic functional connectivity for patients with schizophrenia were inspected.

Based on the data-driven parcellation method, six thalamic subdivisions were defined. Loss of connectivity was observed between several thalamic subdivisions (superior-anterior, ventromedial and dorsolateral part of the thalamus) and the sensorimotor system, anterior cingulate cortex and cerebellum in patients with schizophrenia. A gradual pattern of dysconnectivity was observed across the thalamic subdivisions. Additionally, the altered connectivity negatively correlated with symptom scores and duration of illness in individuals with schizophrenia.

The findings of the study revealed a wide range of thalamic functional dysconnectivity in the CCTCC pathway, increasing our understanding of the relationship between the CCTCC pathway and symptoms associated with schizophrenia, and further indicating a potential alteration pattern in the thalamic nuclei in people with schizophrenia.

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