Tardive dyskinesia (TD) encompasses a constellation of iatrogenic movement disorders caused by antagonism of dopamine receptors (VasanPadhy, 2022). Although manifested primarily in trunk, limb, and hand muscles, TD may affect respiratory muscles in severe cases, diminishing the life expectancy of schizophrenia patients. The annualized incidence of TD was higher in patients treated with first-generation (6.5%) antipsychotics compared to those treated with second-generation (2.6%) antipsychotics (Carbon et al., 2018). The pathogenesis of TD has not been completely understood, and many studies have focused on the hypothesis of dopamine receptor hypersensitivity. However, the hypothesis does not explain why TD persists for years after discontinuing the drug. Antipsychotic drugs and their metabolites disrupt neuronal functions directly through oxidative stress, and accumulating evidence suggests neuronal degeneration and apoptosis as an etiological mechanism of TD. Thus, TD may be associated with changes in cerebral structures and functions beyond the dopaminergic circuits.

Regional homogeneity (ReHo) is a measure used in functional magnetic resonance imaging (fMRI) studies to assess the synchronization or similarity of neural activity within a particular brain region or across multiple regions. The gradient of ReHo characterizes the degree of local functional integration and dissociation in the human brain. Regional differences in local functional homogeneity in brain region pathways contribute to elucidation of our understanding of the principles of functional organization in the brain of TD(JiangZuo, 2016). ReHo represents another measure of the functional integrity of neural circuits, with the assumption that brain voxels that are functionally connected are more likely to be clustered than not. It is based on the assumption that functionally related brain areas show similar levels of activity, or "homogeneity", in their blood oxygen level-dependent (BOLD) signal (Zang et al., 2004). In the context of TD, ReHo may provide a better understanding of the underlying neural mechanisms of the condition. Several fMRI studies have investigated changes in TD patients with the aim of identifying specific brain regions or networks that may be involved in the development or presentation of TD symptoms.

Previous imaging studies showed volumetric increases in the Choroid Plexus and decreases in the Cuneus, Lingual Gyrus, Basal Ganglia, Thalamus, Inferior and Superior Frontal Gyri (Li et al., 2013; Scheepers et al., 2001; Waddington et al., 1995; Newell et al., 1995), white matter abnormalities in Cortico-Basal Ganglia Circuits (Kanzaki et al., 2019; Bai et al., 2009), as well as altered resting state functional connectivity in Postcentral and Inferior Frontal Gyri (Yu et al., 2021). These findings suggest circuit-wide dysfunction in TD. These studies reported regionally homogenous changes in different brain regions, including the basal ganglia, thalamus, and frontal cortex. In particular, the basal ganglia are associated with the pathophysiology of TD, as they are involved in motor control and are known to be affected by long-term use of antipsychotics. By examining patterns of regional homogeneity, we sought to gain insight into the functional connectivity and abnormal neural activity of TD. ReHo is a reliable neurodevelopmental indicator, and studies of schizophrenia have shown that abnormal brain regions of ReHo include the frontal, the temporal, the cingulate gyrus, the cerebellum, the precuneus, the precentral gyrus, the middle occipital gyrus, the insula, and that increased local connectivity is associated with positive syndrome scores in adult schizophrenia(Jiang et al., 2015). At present, there are no ReHo studies on TD. We investigated indicators of neurodevelopmental and local brain functional homogeneity to determine whether they could provide clues about increased or decreased compensation and abnormal functional connectivity of TD motor circuits with increased severity of abnormal involuntary movements. Such an investigation could lead to a better understanding of the disease and possibly help develop more targeted treatments. So in this study, we investigated how whole-brain ReHo may differ among schizophrenia patients with TD and without TD and healthy controls.