Catecholaminergic neuromodulation shapes intrinsic MRI functional connectivity in the human brain

The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain
regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed
anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of
brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleusnorepinephrine
system, which send diffuse projectionsto most parts ofthe forebrain. Here, we systematically characterizedthe effects of
endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebocontrolled
crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter
blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First,
atomoxetine reducedthe strength ofinter-regional correlations acrossthree levels of spatial organization,indicatingthat catecholamines
reducethe strength of functional interactions during rest. Second,this modulatory effect on intrinsic correlations exhibited a substantial
degree of spatial specificity:the decrease infunctional connectivity showed an anterior–posterior gradient inthe cortex, depended onthe
strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state
networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We concludethat neuromodulation is
an important factor shaping the topography of intrinsic functional connectivity.