Longitudinal changes in striatal regional homogeneity and their clinical correlates in treatment-resistant schizophrenia

Schizophrenia is a complex and debilitating neurodevelopmental disorder characterized by heterogeneous clinical presentations and varying responses to pharmacological interventions. Among the most challenging clinical populations are those with treatment-resistant schizophrenia (TRS), a condition defined by inadequate symptom relief despite multiple trials of antipsychotic medications. While striatal dysfunction has long been hypothesized as a core pathophysiological feature of schizophrenia, particularly through the lens of the dopamine hypothesis, its longitudinal evolution during active treatment in resistant populations remains insufficiently understood [1]. To address this gap, the current study utilized Regional Homogeneity (ReHo)—a resting-state functional magnetic resonance imaging (rs-fMRI) metric that measures the local synchronization of spontaneous blood-oxygen-level-dependent (BOLD) signals. ReHo provides critical insights into regional functional integration and the integrity of local neural networks, which may be disrupted in psychiatric conditions.

This study systematically evaluated longitudinal ReHo changes in TRS and Non-TRS (NTRS) patients to identify specific local connectivity markers that correlate with fluctuations in clinical symptom severity. The research involved 29 TRS and 30 NTRS patients, all of whom underwent rs-fMRI scanning at baseline (BS) and following an 18-week clinical follow-up (FU) period. Neuroimaging data were rigorously processed using the DPARSFA toolbox, with the Kendall coefficient of concordance (KCC) employed to calculate ReHo maps for each participant. Following standard preprocessing steps—including slice-timing correction, motion realignment, nuisance regression (e.g., white matter, CSF signals, and head motion parameters), and spatial smoothing—a longitudinal analysis of variance (ANOVA) was performed to identify significant group-by-time interactions in ReHo across the whole brain. To link these neuroimaging findings to clinical outcomes, Pearson correlation analyses were conducted between changes in ReHo (ΔReHo) within the identified regions and changes in the Positive and Negative Syndrome Scale (PANSS) scores (ΔPANSS).

At baseline, the TRS group exhibited significantly higher PANSS scores across all domains compared to the NTRS group (p < 0.001). Significant longitudinal interactions in ReHo were identified in the left ventral putamen (venPUT) and left dorsal putamen (dorPUT). For the total sample, ΔReHo in the venPUT showed significant positive correlations with ΔPANSS total (r = 0.510, p < 0.001), positive symptoms (r = 0.409, p = 0.001), and general symptoms (r = 0.334, p = 0.009). Notably, within the TRS group, ΔReHo in the venPUT was specifically associated with improvements in ΔPANSS total (r = 0.467, p = 0.011) and positive symptoms (r = 0.458, p = 0.013). Similarly, ΔReHo in the dorPUT within the TRS group correlated with reductions in positive symptoms (r = 0.441, p = 0.017).

Our findings highlight the crucial role of the putamen in the pathophysiology and treatment response of TRS. The significant correlation between increased local synchronization in the ventral/dorsal putamen and decreased positive symptoms suggests that striatal functional reorganization is a key driver of clinical recovery, even in treatment-resistant patients. These results provide neurobiological evidence that monitoring striatal ReHo may serve as a potential biomarker for predicting clinical trajectories and refining therapeutic strategies for TRS.

References

1. D’Ambrosio E, Jauhar S, Kim S, Veronese M, Rogdaki M, Pepper F, Bonoldi I, Kotoula V, Kempton MJ, Turkheimer F, Kwon JS, Kim E, Howes OD. The relationship between grey matter volume and striatal dopamine function in psychosis: a multimodal 18F-DOPA PET and voxel-based morphometry study. Mol Psychiatry. 2021;26(4):1332-1345.