Disrupted subcortical functional connectome gradient in drug-naïve first-episode schizophrenia and the normalization effects after antipsychotic treatment

Abstract

Antipsychotics are thought to improve schizophrenia symptoms through the antagonism of dopamine D2 receptors, which are abundant mainly in subcortical regions. By introducing functional gradient, a novel approach to identify hierarchy alterations by capturing the similarity of whole brain fucntional connectivity (FC) profiles between two voxels, the present study aimed to characterize how the subcortical gradient is associated with treatment effects and response in first-episode schizophrenia in vivo. Two independent samples of first-episode schizophrenia (FES) patients with matched healthy controls (HC) were obtained: the discovery dataset included 71 patients (FES_0W) and 64 HC at baseline, and patients were re-scanned after either 6 weeks (FES_6W, N = 33) or 12 months (FES_12M, N = 57) of antipsychotic treatment, of which 19 patients finished both 6-week and 12-month evaluation. The validation dataset included 22 patients and 24 HC at baseline and patients were re-scanned after 6 weeks. Gradient metrics were calculated using BrainSpace Toolbox. Voxel-based gradient values were generated and group-averaged gradient values were further extracted across all voxels (global), three systems (thalamus, limbic and striatum) and their subcortical subfields. The comparisons were conducted separately between FES_0W and HC for investigating illness effects, and between FES_6W/FES_12M and FES_0W for treatment effects. Correlational analyses were then conducted between the longitudinal gradient alterations and the improvement of clinical ratings. Before treatment, schizophrenia patients exhibited an expanded range of global gradient scores compared to HC which indicated functional segregation within subcortical systems. The increased gradient in limbic system and decreased gradient in thalamic and striatal system contributed to the baseline abnormalities and led to the disruption of the subcortical functional integration. After treatment, these disruptions were normalized and the longitudinal changes of gradient scores in limbic system were significantly associated with symptom improvement. Similar illness and treatment effects were also observed in the validation dataset. By measuring functional hierarchy of subcortical organization, our findings provide a novel imaging marker that is sensitive to treatment effects and may make a promising indicator of treatment response in schizophrenia.

Fig. 1. Group differences of the group-averaged subcortical gradient scores at global- and system-levels between schizophrenia at baseline and healthy control as well as the longitudinal alterations in 6-week and 12-month follow-up relative to baseline abnormalities.

a Global histograms showing that gradient range was expanded in schizophrenia at baseline, but normalized after 6-week and 12-month antipsychotic treatment. b The group-averaged maps of principal gradient in discovery dataset, including HC, schizophrenia at baseline as well as after 6-week and 12-month treatment. c System-based histograms showing that the increased limbic and decreased thalamic and striatal gradient contributed to the baseline abnormal global gradient, and the limbic system was normalized the most after both 6-week and 12-month treatment. Blue arrows represent decreased trend of gradient scores while red arrow represents increased trend in system-level in patients at baseline compared to HC. HC healthy controls.

Fig. 2. Associations of longitudinal subcortical gradient score changes after 12-month treatment and symptom improvement in schizophrenia patients.

a Group differences of group-averaged gradient in limbic system in patients between 12-month and baseline. b Longitudinal changes in limbic system were associated with the improvement of GAF, PANSS total scores, disorganization and excitement subscales. c Group differences of group-averaged gradient in subfields of limbic system in patients between 12-month and baseline. ★ The negative correlation coefficient represents consistent improvement in gradient scores and clinical symptoms (both higher scores of the GAF and the lower scores of the PANSS indicated improvement of functioning and symptoms, respectively). HC healthy controls, -rh right hemisphere, -lh left hemisphere, aHIP anterior hippocampus, pHIP posterior hippocampus, lAMY lateral amygdala, mAMY medial amygdala, GAF Global Assessment of Functioning, PANSS Positive and Negative Syndrome Scale.