Irritability is present in multiple disorders in youth, suggesting that it is a dimension of psychopathology that cuts across traditional categorical diagnostic boundaries. We propose to investigate how abnormal brain development produces dimensionally defined symptoms of irritability by leveraging the resources and data of the Philadelphia Neurodevelopmental Cohort (PNC). As part of the PNC, a large sample (n=1,601) of youth ages 8-21 completed cross-sectional neuroimaging along with clinical and cognitive phenotyping, including screening questions for irritability. We will conduct longitudinal follow-up multi-modal neuroimaging in 140 youth with diverse psychopathology who screened positive for symptoms of irritability, as well as 60 matched typically developing controls. We will repeat the imaging sequences performed at baseline including T1 imaging of brain structure, arterial spin labeled MRI of cerebral perfusion, a resting-state scan of functional connectivity, and a fractal version of the n-back working memory task. These longitudinal measures will be supplemented by the cross-sectional acquisition of sequences that are particularly relevant to irritability, including a high temporal resolution resting state sequence to examine dynamic executive-affective connectivity as well as a social affective feedback fMRI paradigm that recruits both the ventral striatum and the amygdala. The comprehensive assessment of brain structure and function provided by these measures will enable testing a model which posits that irritability results an evolving combination of executive deficits, affective dysregulation, and executive-affective dysconnectivity. Accordingly, in Aim 1 we will delineate how longitudinal changes in brain development as measured by multi-modal imaging are associated with irritability.
In Aim 2, we will demonstrate that irritability is associated abnormal affective activation and connectivity using specialized functional imaging sequences acquired at follow-up.
In Aim 3, as prior work has demonstrated sex differences in the both irritability and patterns of brain development, we will examine how brain phenotypes associated with irritability differ by sex. Finally, in Exploratory Aim 4 we will use advanced multivariate pattern analysis techniques to integrate high-dimensional multi-modal imaging data and predict irritability. This application capitalizes on the PI's clinical experience, expertise in multi-modal developmental neuroimaging, established collaborations, and intimate familiarity with the PNC dataset. Through the proposed multi-level analysis, this innovative research will provide a substantial advance in our understanding of the neurodevelopmental substrates of irritability.
Irritability is a debilitating dimension of psychopathology that is present in multiple psychiatric disorders. Greater understanding of how abnormalities in brain development during youth produce symptoms of irritability may be critical for the development of earlier and more effective treatments. This would benefit public health by reducing the great costs of irritability to individuals and society at large.
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