Prefrontal Cortical Connectivity Mediates Locus Coeruleus Noradrenergic Regulation of Inhibitory Control in Older Adults

Response inhibition is a core executive function enabling adaptive behavior in dynamic environments. Human and animal models indicate that inhibitory control and control networks are modulated by noradrenaline, arising from the locus coeruleus. The integrity (i.e., cellular density) of the locus coeruleus noradrenergic system can be estimated from magnetization transfer (MT)-sensitive magnetic resonance imaging (MRI), in view of neuromelanin present in noradrenergic neurons of older adults. Noradrenergic psychopharmacological studies indicate noradrenergic modulation of prefrontal and frontostriatal stopping-circuits in association with behavioral change. Here, we test the noradrenergic hypothesis of inhibitory control, in healthy adults. We predicted that locus coeruleus integrity is associated with age-adjusted variance in response inhibition, mediated by changes in connectivity between frontal inhibitory control regions. In a preregistered analysis, we used MT MRI images from N = 63 healthy humans aged above 50 years (of either sex) who performed a Stop-Signal Task (SST), with atlas-based measurement of locus coeruleus contrast. We confirm that better response inhibition is correlated with locus coeruleus integrity and stronger connectivity between presupplementary motor area (preSMA) and right inferior frontal gyrus (rIFG), but not volumes of the prefrontal cortical regions. We confirmed a significant role of prefrontal connectivity in mediating the effect of individual differences in the locus coeruleus on behavior, where this effect was moderated by age, over and above adjustment for the mean effects of age. Our results support the hypothesis that in normal populations, as in clinical settings, the locus coeruleus noradrenergic system regulates inhibitory control. SIGNIFICANCE STATEMENT We show that the integrity of the locus coeruleus, the principal source of cortical noradrenaline, is related to the efficiency of response inhibition in healthy older adults. This effect is in part mediated by its effect on functional connectivity in a prefrontal cortical stopping-network. The behavioral effect, and its mediation by connectivity, are moderated by age. This supports the psychopharmacological and genetic evidence for the noradrenergic regulation of behavioral control, in a population-based normative cohort. Noradrenergic treatment strategies may be effective to improve behavioral control in impulsive clinical populations, but age, and locus coeruleus integrity, are likely to be important stratification factors.