Abstract
Background
The cerebral cortex is organised hierarchically along an axis that spans unimodal sensorimotor to transmodal association areas. This hierarchy is often characterized using low-dimensional embeddings, termed gradients, of inter-regional functional coupling estimates measured with resting-state functional magnetic resonance imaging (fMRI). Such analyses may offer insights into the pathophysiology of schizophrenia, which is frequently linked to dysfunctional interactions between association and sensorimotor areas.
Methods
To examine disruptions of hierarchical cortical function across distinct stages of psychosis, we applied diffusion map embedding to two independent fMRI datasets: one comprised 114 patients with early psychosis and 48 controls, and the other comprising 50 patients with established schizophrenia and 121 controls. We then analyzed the primary sensory-fugal and secondary visual-to-sensorimotor gradients of each participant in both datasets.
Results
There were no significant differences in regional gradient scores between patients with early psychosis and controls. Patients with established schizophrenia showed significant differences in the secondary, but not primary, gradient relative to controls. Gradient differences in schizophrenia were characterized by lower within-network dispersion in the Dorsal Attention (pFDR<.001), Visual (pFDR=.003), Frontoparietal (pFDR=.018), and Limbic (pFDR=.020) networks and lower between-network dispersion between the Visual network and other networks (pFDR<.001).
Conclusions
These findings indicate that differences in cortical hierarchical function occur along the secondary visual-to-sensorimotor axis rather than the primary sensory-fugal axis, as previously thought. The absence of differences in early psychosis suggests that visual-sensorimotor abnormalities may emerge as the illness progresses.
Introduction
Converging evidence from tract-tracing, lesion, and physiological studies indicate cortical systems are organised along a hierarchical axis, anchored by unimodal sensorimotor areas at one end and transmodal association areas at the other (1,2). Information-processing along this hierarchy is thought to allow the integration of incoming sensory signals with a diverse range of multimodal interoceptive and exteroceptive signals (3,4). Accordingly, disturbances to this hierarchy are thought to negatively impact cognitive and clinical outcomes (5, 6, 7, 8, 9).
The symptoms of psychosis are thought to arise from impaired brain connectivity and a dissolution of integrative, higher-order cognitive processes (10, 11, 12). Both sensory deficits and impairments in executive control and attention have been identified in patients, suggesting a disruption of hierarchical signaling between cortical systems may contribute to disease pathophysiology (13, 14, 15, 16, 17, 18).
The hierarchical organisation of cortical function can be investigated using various dimensionality reduction techniques, which decompose estimates of inter-regional functional coupling (FC) measured with resting-state functional magnetic resonance imaging (fMRI) into orthogonal axes of variation (1,7). These axes define smoothly varying gradients of regional FC profiles, ordered by the amount of variance in FC similarity that they explain (19, 20, 21). The dominant (primary) gradient explains the most variance and represents an axis spanning visual and other sensorimotor areas to the default mode network (DMN) and other transmodal regions (1,22), consistent with classical descriptions of the sensory-fugal axis of cortical organisation (3,23). The secondary gradient represents an axis spanning sensorimotor areas to visual areas, differentiating unimodal areas situated at approximately the same level in the cortical hierarchy (3).
Recent work suggests schizophrenia patients possess a contracted primary sensory-fugal gradient (24), suggesting reduced differentiation between transmodal and sensorimotor areas. However, whether the secondary, sensorimotor-visual gradient is affected remains unknown. Moreover, it is unclear whether changes in hierarchical cortical organisation are apparent from the earliest stages of psychosis or emerge only with prolonged illness. To address these questions, we investigated the organisation of the cortical hierarchy by comparing the primary and secondary FC gradients of participants in two independent cohorts––one with patients in the early stages of psychosis and another with patients with established schizophrenia––allowing us to determine whether disrupted hierarchical function persists across different illness stages. Given the prominent role ascribed to disruptions of hierarchical processing in the onset of psychotic symptoms (13,14,18), we hypothesized that both cohorts of early psychosis and schizophrenia will show disrupted organisation of the dominant sensory-fugal gradient, characterized by a reduced functional differentiation between sensorimotor and transmodal association areas.
Methods and Materials
Participants
We used open-access neuroimaging and behavioral data from 178 participants from the Human Connectome Project for Early Psychosis (HCP-EP) dataset (57 controls; 121 early psychosis patients) (25) and 171 participants from the UCLA Consortium of Neuropsychiatric Phenomics (CNP) dataset (121 controls; 50 schizophrenia patients) (26). See Tables 1-3 for demographic and clinical information across both datasets….
