Intrinsic Connectivity Network-Based Classification and Detection of Psychotic Symptoms in Youth With 22q11.2 Deletions

Abstract

22q11.2 Deletion syndrome (22q11DS) is a genetic disorder associated with numerous phenotypic consequences and is one of the greatest known risk factors for psychosis. We investigated intrinsic-connectivity-networks (ICNs) as potential biomarkers for patient and psychosis-risk status in 2 independent cohorts, UCLA (33 22q11DS-participants, 33 demographically matched controls), and Syracuse (28 22q11DS, 28 controls). After assessing group connectivity differences, ICNs from the UCLA cohort were used to train classifiers to distinguish cases from controls, and to predict psychosis risk status within 22q11DS; classifiers were subsequently tested on the Syracuse cohort. In both cohorts we observed significant hypoconnectivity in 22q11DS relative to controls within anterior cingulate (ACC)/precuneus, executive, default mode (DMN), posterior DMN, and salience networks. Of 12 ICN-derived classifiers tested in the Syracuse replication-cohort, the ACC/precuneus, DMN, and posterior DMN classifiers accurately distinguished between 22q11DS and controls. Within 22q11DS subjects, connectivity alterations within 4 networks predicted psychosis risk status for a given individual in both cohorts: the ACC/precuneus, DMN, left executive, and salience networks. Widespread within-network-hypoconnectivity in large-scale networks implicated in higher-order cognition may be a defining characteristic of 22q11DS during adolescence and early adulthood; furthermore, loss of coherence within these networks may be a valuable biomarker for individual prediction of psychosis-risk in 22q11DS.

Large-scale brain network dynamics provide a measure of psychosis and anxiety in 22q11.2 deletion syndrome

“…Despite these promises of dynamic fMRI analysis, functional neuroimaging research in 22q11DS has so far mostly focused on static functional features (17,80,54,84,55), often targeting only specific functional networks such as the DMN (66,85). The studies who explicitly investigated psychotic symptoms in 22q11DS showed correlations of DMN dysconnectivity with prodromal psychotic symptoms (17), as well as successful discrimination between patients at high vs. low risk based whole-brain rs-fMRI (80) and hypoconnectivity of DMN, SN, anterior cingulate cortex (ACC) and frontoparietal network (FPN; 84).…”

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

“…However, few studies have investigated the effect of 'neuropsychiatric' CNVs on FC. Dysconnectivity of thalamic-hippocampal circuitry 13 has been reported in 22q11.2 deletion carriers, with prominent under-connectivity of the default mode network (DMN), which was predictive of prodromal psychotic symptomatology 14,15 . Impaired connectivity of long-range connections within the DMN has also been reported by other studies 16 .…”

Frontal dysconnectivity in 22q11.2 deletion syndrome: an atlas-based functional connectivity analysis

“…Results of these studies indicate anomalous connectivity in frontal lobe connections [ 20 ] and parieto–occipital connections [ 20 – 22 ]. Decreases in functional connectivity have also been observed, in partially overlapping samples, in the default mode [ 23 – 26 ], salience [ 24 ] and frontal–parietal networks [ 22 , 24 ]. In a modularity analysis of overall functional network organization, Scariati and colleagues [ 27 ] observed increased modular segregation across superior parietal, frontal and inferior temporal lobes in individuals with 22q11DS.…”

“…In a modularity analysis of overall functional network organization, Scariati and colleagues [ 27 ] observed increased modular segregation across superior parietal, frontal and inferior temporal lobes in individuals with 22q11DS. Associations between anomalous functional connectivity in 22q11DS and increased symptoms of psychosis have been observed in most [ 20 , 22 , 24 ], but not all studies [ 25 ].…”