Bearden, C. E. | bioRxiv Science

bioRxiv2018

Transient patterns of functional dysconnectivity in youth with psychosis spectrum symptoms

Psychosis spectrum disorders are conceptualized as neurodevelopmental disorders accompanied by disruption of large-scale functional brain networks. Both static and dynamic dysconnectivity have been described in patients with schizophrenia and, more recently, in help-seeking individuals at clinical high-risk for psychosis. Less is known, however, about developmental aspects of dynamic functional network connectivity (FNC) associated with psychotic symptoms (PS) in the general population. Here, we investigate resting state fMRI data using established dynamic FNC methods in the Philadelphia Neurodevelopmental Cohort (ages 8-22), including 129 participants experiencing PS and 452 participants without PS (non-PS).\n\nApplying a sliding window approach and k-means clustering, 5 dynamic states with distinct whole-brain connectivity patterns were identified. PS-associated dysconnectivity was most prominent in states characterized by synchronization or antagonism of the default mode network (DMN) and cognitive control (CC) domains. Hyperconnectivity between DMN, salience, and CC domains in PS youth only occurred in a state characterized by synchronization of the DMN and CC domains, a state that also becomes less frequent with age. However, dysconnectivity of the sensorimotor and visual systems in PS youth was revealed in other transient states completing the picture of whole-brain dysconnectivity patterns associated with PS.\n\nOverall, state-dependent dysconnectivity was observed in PS youth, providing the first evidence that disruptions of dynamic functional connectivity are present across a broader psychosis continuum.

neuroscience↗

bioRxiv2017

Reciprocal Disruptions in Thalamic and Hippocampal Resting-State Functional Connectivity in Youth with 22q11.2 Deletions

22q11.2 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.\n\nSIGNIFICANCE 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.

neuroscience↗