ABSTRACT22q11.2 deletion syndrome (22q11DS) is a recurrent copy number variant (CNV) with high penetrance for developmental neuropsychiatric disorders. Study of individuals with 22q11DS therefore may offer key insights into neural mechanisms underlying such complex illnesses. Resting-state functional MRI (rs-fMRI) studies in idiopathic schizophrenia have consistently revealed disruption of thalamic and hippocampal circuitry. Here, we sought to test whether this circuitry is similarly disrupted in the context of this genetic high-risk condition. To this end, resting-state functional connectivity patterns were assessed in a sample of young men and women with 22q11DS (n=42) and demographically matched healthy controls (n=39). Neuroimaging data were acquired via single-band protocols, and analyzed in line with methods provided by the Human Connectome Project (HCP). We computed functional relationships between individual-specific anatomically-defined thalamic and hippocampal seeds and all gray matter voxels in the brain. Whole-brain type I error protection was achieved through nonparametric permutation-based methods. 22q11DS patients displayed reciprocal disruptions in thalamic and hippocampal functional connectivity relative to control subjects. Thalamo-cortical coupling was increased in sensorimotor cortex, and reduced across associative networks. The opposite effect was observed for the hippocampus in regards to sensory and associative network connectivity. The thalamic and hippocampal dysconnectivity observed in 22q11DS suggest that high genetic risk for psychiatric illness is linked with disruptions in large-scale cortico-subcortical networks underlying higher-order cognitive functions. These effects highlight the translational importance of large-effect CNVs for informing mechanisms underlying neural disruptions observed in idiopathic developmental neuropsychiatric disorders.SIGNIFICANCE STATEMENTInvestigation of neuroimaging biomarkers in highly penetrant genetic syndromes represents a more biologically tractable approach to identify neural circuit disruptions underlying developmental neuropsychiatric conditions. 22q11.2 deletion syndrome confers particularly high risk for psychotic disorders, and is thus an important translational model in which to investigate systems-level mechanisms implicated in idiopathic illness. Here, we show resting-state fMRI evidence of large-scale sensory and executive network disruptions in youth with 22q11DS. In particular, this study provides the first evidence that these networks are disrupted in a reciprocal fashion with regard to the functional connectivity of the thalamus and hippocampus, suggesting circuit-level dysfunction.
Pilot Study on Resting-State Functional Connectivity under the Effects of Familial Loading in People at Ultra-High Risk for Psychosis
