Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain

Abstract

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 projections to most parts of the forebrain. Here, we systematically characterized the 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 reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the 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 conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity.

Network structure of the mouse brain connectome with voxel resolution

“…Importantly, the observed spatial correspondences between the structural and functional topography of the mouse connectome argue for a critical role for these neuromodulatory nuclei in shaping large-scale neural activity. This notion is consistent with the observation that catecholaminergic and serotonergic activity critically control functional network topography and dynamics 30,31,49 . Together with the observation that connector hub removal critically diminishes network communicability, these results suggest that that ascending modulatory systems are strategically wired as central orchestrators of large-scale inter-modular communication, a network property that might be key in ensuring the effective and finely-tuned control of complex behavioral and physiological states exerted by these systems.…”

“…Of note, the high correspondence between functional and structural modules supports a role for connector nodes as strategic orchestrators of brain-wide network activity 29 . In the light of this, our observations suggests that ascending modulatory system are strategically wired as key orchestrators of inter-modular activity, a finding consistent with emerging evidence pointing at a pivotal contribution of cathecolaminergic neurotransmission in modulating functional network activity and dynamics 30,31 .…”

Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits

“…Furthermore, a resting state fMRI study in healthy subjects reported a FC decrease induced by atomoxetine, i.e. a relatively selective NET blocker, predominantly in the posterior brain regions including the visual system [78]. Another fMRI study using a n-back task in healthy volunteers reported atomoxetine-induced FC changes in the frontoparietal network, including areas such as the precentral gyrus and the precuneus, during working-memory processing [79].…”

Amplification and Suppression of Distinct Brain-wide Activity Patterns by Catecholamines

“…Fewer studies have assessed catecholaminergic modulation of large-scale brain network 761 dynamics. Pharmacological fMRI studies in monkeys and humans have shown that catecholamines 762 alter the strength of correlations between distant brain regions (Hermans et al, 2011;Guedj et al, 763 2016;van den Brink et al, 2016;Warren et al, 2016;Hernaus et al, 2017). While 'resting-state' 764 studies have reported catecholamine-induced decreases in correlation strength (van den Brink et al, 765 2016;Guedj et al, 2017), task-based studies have reported increases Hernaus et 766 al., 2017), or the converse for noradrenergic antagonism (Hermans et al, 2011).…”