Relationships between local metabolic activity and distributed functional connectivity in major depressive disorder

Functional neuroimaging studies have described changes in local activity or in distributed connectivity in Major Depressive Disorder (MDD). We studied the interactions between these levels of neural organization to reveal novel pathobiological signatures of MDD. We scanned 21 unmedicated MDD subjects and 21 matched non-depressed controls at rest with simultaneous ¹⁸fluorodeoxyglucose PET (FDG-PET, to measure local metabolic activity), and resting-state functional Magnetic Resonance Imaging (rsfMRI, to measure hemodynamic functional connectivity, FC). We first identified regions of interest (ROIs) with increased (hypermetabolic) or decreased (hypometabolic) glucose metabolism in depressed compared to non-depressed subjects. Next, we used these hypermetabolic and hypometabolic regions as seed-based ROIs to derive FC maps, and compared these maps across depressed and non-depressed subjects. Depressed subjects demonstrated hypermetabolism in regions partially overlapping with the cingulo-opercular network, and hypometabolism in regions partially overlapping with the default network. In depressed subjects, hypermetabolic ROIs displayed stronger FC to portions of the frontostriatal salience network. Interestingly, hypometabolic ROIs displayed weaker FC with almost identical frontostriatal salience network regions. This work further emphasizes network-level metabolic and hemodynamic functional connectivity changes in MDD. More specifically, our findings suggest that local metabolic activity is up- or down-regulated in a distributed fashion in depression and that these metabolic changes are associated with comparable increases and decreases in functional coupling to the frontostriatal salience network-further bolstering the putative pathogenic importance of this network in MDD. Clinical Trials registration number: NCT01931995.