More Severe Brain Network Hierarchy Disorganization in Treatment-Naive Deficit Compared to Non-deficit Schizophrenia and Underlying Neurotransmitter Associations

Abstract

Background and Hypothesis Deficit schizophrenia (DS) represents a distinct entity characterized by primary and enduring negative symptoms, yet the neurobiological differences between DS and non-DS (NDS) remain undetermined. Using a gradient-based approach, we hypothesize that DS and NDS will exhibit convergent and divergent brain functional hierarchy patterns, each with a specific underlying neurotransmitter architecture. Study Design Resting-state functional magnetic resonance imaging images were acquired from 44 treatment-naive DS, 55 treatment-naive NDS, and 60 matched healthy controls (HCs). Gradient metrics were calculated using the BrainSpace toolbox. The spatial correlation between gradient abnormalities in DS or NDS and density maps of 10 neurotransmitters derived by the JuSpace toolbox was analyzed to link the neuroimaging to underlying neurotransmitter information. Study Results Both DS and NDS exhibited compressed gradient patterns compared to HC, suggesting reduced network differentiation, with more severe disorganization in DS. The ventral attention network was associated with depression symptoms in DS, whereas the visual network was related to total, general, and paranoid symptom scores in NDS. Moreover, spatial correlation of neurotransmitter analysis revealed that the gradient alterations of DS were primarily related to the serotonergic system while those of NDS were predominantly associated with the dopamine system. Conclusions The study suggests that independent from the potential effects of antipsychotic medication, DS and NDS are characterized by different neuropathology in brain hierarchy patterns, potentially linked to neurochemical metabolic distinction. Our findings support the hypothesis that DS is a distinct subtype versus NDS from neurodevelopmental perspective.