title: 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 ceruleus-norepinephrine 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 placebo-controlled 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.
  
  
  
  The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system.
authors.affiliation: Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands, Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands, r.l.van.den.brink@fsw.leidenuniv.nl.
authors.forename: Ruud L
authors.identifier: 0000-0002-3142-7248
authors.initials: RL
authors.lastname: van den Brink
authors.affiliation: Department of Neurophysiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: Thomas
authors.identifier: 0000-0001-9561-3085
authors.initials: T
authors.lastname: Pfeffer
authors.affiliation: Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands, Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands.
authors.forename: Christopher M
authors.identifier: 0000-0002-2541-7246
authors.initials: CM
authors.lastname: Warren
authors.affiliation: Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands, Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands.
authors.forename: Peter R
authors.identifier: 0000-0003-1963-185X
authors.initials: PR
authors.lastname: Murphy
authors.affiliation: Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands, Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands.
authors.forename: Klodiana-Daphne
authors.initials: KD
authors.lastname: Tona
authors.affiliation: Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands, Department of Psychiatry and.
authors.forename: Nic J A
authors.initials: NJ
authors.lastname: van der Wee
authors.affiliation: Department of Psychiatry and.
authors.forename: Eric
authors.identifier: 0000-0001-8874-2292
authors.initials: E
authors.lastname: Giltay
authors.affiliation: Department of Psychiatry and.
authors.forename: Martijn S
authors.initials: MS
authors.lastname: van Noorden
authors.affiliation: Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands, Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands, Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Serge A R B
authors.identifier: 0000-0001-6351-4779
authors.initials: SA
authors.lastname: Rombouts
authors.affiliation: Department of Neurophysiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany, Department of Psychology, University of Amsterdam, 1012 WX, Amsterdam, The Netherlands, and Amsterdam Center for Brain and Cognition, Institute for Interdisciplinary Studies, 1001 NK Amsterdam, The Netherlands.
authors.forename: Tobias H
authors.initials: TH
authors.lastname: Donner
authors.affiliation: Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands, Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands.
authors.forename: Sander
authors.identifier: 0000-0003-2418-3879
authors.initials: S
authors.lastname: Nieuwenhuis
mesh_terms: D059331:Adrenergic Neurons / Q000502:physiology*; D000328:Adult; D002395:Catecholamines / Q000378:metabolism*; D002540:Cerebral Cortex / Q000502:physiology*; D063132:Connectome / Q000379:methods*; D059290:Dopaminergic Neurons / Q000502:physiology*; D004311:Double-Blind Method; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009415:Nerve Net / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology; D015990:Placebo Effect; D012146:Rest / Q000502:physiology; D055815:Young Adult
chemical_list: D002395:Catecholamines
keywords: catecholamines; functional connectivity; gain; neuromodulation; norepinephrine; resting-state fMRI