Abstract
Converging evidence indicates that dysregulated cortico-subcortical connectivity underpins core cognitive impairment in schizophrenia (SCZ). However, the mechanistic basis linking this disrupted brain function to cognitive deficits remains elusive. We hypothesized that dysfunction within the hippocampal-thalamocortical circuitry mediates the impact of peripheral inflammation on cognitive deficits in SCZ. We recruited 62 drug-native patients with SCZ and 44 age and sex-matched healthy controls (HCs), assessing: serum levels of cytokines, cognition using the MATRICS Consensus Cognitive Battery, and resting-state functional connectivity (FC) and functional connectivity network (FCN) features. Correlation and mediation analyses were employed to examine relationships among peripheral inflammation, brain functional alterations, and cognitive deficits. The findings revealed reduced FC in SCZ between the right subiculum of the hippocampus and the anterior division of the right parahippocampal gyrus (aPaHC), as well as the entorhinal cortex and the left lingual gyrus/precuneus. Conversely, the thalamus exhibited aberrant hyperconnectivity with widespread areas, including the Cornu Ammonis of the hippocampus, right lateral occipital cortex, intraparietal sulcus (IPS), and sensorimotor areas. Conjunction analysis identified distinct disruptions within hippocampal-thalamo-visual circuitry, suggesting that an imbalance in thalamo-visual and intra-hippocampal connectivity may mediate the relationship between peripheral inflammation (e.g., IL-4, CCL-2) and working memory dysfunction. This study advances our understanding of the role of peripheral inflammation in SCZ, revealing complex cross-domain interactions between pathophysiological changes (e.g., dysregulated peripheral immunity and circuit-specific dysfunction) and behavioral features. Our findings highlight a novel combinatorial therapeutic strategy-integrating cytokine-specific agents (e.g., for CCL-2 and IL-4) with circuit-directed neuromodulation of the dysfunctional hippocampal-thalamic-visual circuitry, thereby ameliorating cognitive deficits in SCZ.