| Summary: | White matter (WM) microstructure deficit may be an underlying factor in the brain dysconnectivity hypothesis of schizophrenia using diffusion tensor imaging (DTI). However, WM dysfunction is unclear in schizophrenia. This study aimed to investigate the association between structural deficits and functional disturbances in major WM tracts in schizophrenia. Using functional magnetic resonance imaging (fMRI) and DTI, we developed the skeleton-based WM functional analysis, which could achieve voxel-wise function–structure coupling by projecting the fMRI signals onto a skeleton in WM. We measured the fractional anisotropy (FA) and WM low-frequency oscillation (LFO) and their couplings in 93 schizophrenia patients and 122 healthy controls (HCs). An independent open database (62 schizophrenia patients and 71 HCs) was used to test the reproducibility. Finally, associations between WM LFO and five behaviour assessment categories (cognition, emotion, motor, personality and sensory) were examined. This study revealed a reversed pattern of structure and function in frontotemporal tracts, as follows. (a) WM hyper-LFO was associated with reduced FA in schizophrenia. (b) The function–structure association was positive in HCs but negative in schizophrenia patients. Furthermore, function–structure dissociation was exacerbated by long illness duration and severe negative symptoms. (c) WM activations were significantly related to cognition and emotion. This study indicated function–structure dys-coupling, with higher LFO and reduced structural integration in frontotemporal WM, which may reflect a potential mechanism in WM neuropathologic processing of schizophrenia. © 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.
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