Cross-species neuroimaging intermediate phenotypes deepen our understanding of depression

Abstract Multiple genetic variants and their interplay with environmental factors have hindered the progress of mental disease research and the development of effective markers of neuropsychiatric disorders. Intermediate phenotypes like neuroimaging brain patterns offer unique opportunities to understand multifaceted etiologies of neuropsychiatric diseases such as depression. Neuroimaging intermediate phenotypes bridging etiologic differences and disease behavioral features may facilitate translational applications of animal models to humans with depression. We identified cross-species neuroimaging patterns of the amplitude of low-frequency fluctuations (ALFF) that correlated with anhedonia in rodent genetic and stress models of depression and depressed individuals. Compared to controls, converse ALFF patterns in subcortical and sensorimotor regions were found between P11 knockout mice and chronic unpredictable mild stress rats. Similarly, two ALFF subtypes with converse patterns in frontal, subcortical, and sensorimotor regions were identified and validated in two independent human cohorts for depression. Importantly, anhedonia was significantly increased across all rodent models and human subtypes when compared to controls, despite differences in ALFF patterns. Further, anhedonia correlated with subcortical-sensorimotor ALFF in rodent models and human cohorts. Thus, subcortical-sensorimotor ALFF may serve as an intermediate phenotype that bridges etiologic differences and anhedonia in depression. These results deepened our knowledge of disease mechanisms underlying depression which can be explored in translational research and clinical applications treating depression and other psychiatric disorders.