Dynamic reconfiguration of subunits from the hippocampal-amygdala complex indicate patterns of psychosis vulnerability in 22q11.2 deletion syndrome

The hippocampus and amygdala form a tightly integrated circuit supporting memory-emotion integration and stress regulation, critically implicated in psychosis development. However, the maturation of the hippocampus-amygdala (HIP-AMY) complex as a functional unit remains poorly understood. 22q11.2 deletion syndrome (22q11DS), with increased risk of schizophrenia, provides a valuable model to study its neurodevelopmental trajectories. A prospective longitudinal cohort of 133 individuals with 22q11DS and 150 healthy controls (HC) underwent neuroimaging and psychiatric assessments approximately every three years. Resting-state fMRI data were analysed using a data-driven clustering approach to identify transient states of dynamic functional connectivity linked to the activation of specific ensembles of HIP-AMY nuclei. State occurrences over age were compared between 22q11DS and HC and between 22q11DS individuals with and without positive psychotic symptoms (PPS+ and PPS-). Seven HIP-AMY states were identified, three showing significant and one trend-level age-by-diagnosis interaction. Importantly, the occurrence of a CA3-centromedial amygdala driven state showing co-activation of limbic and thalamo-striatal salience hubs decreased over age in HC, but remained elevated in 22q11DS. This divergence was reflected within 22q11DS, with PPS- showing a decrease and PPS+ a modest increase. The persistence of this pattern over development may provide a dynamic signature of emergence of psychosis.