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Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain

Ruud L. van den Brink, Thomas Pfeffer, Christopher M. Warren, Peter R. Murphy, Klodiana-Daphne Tona, Nic J. A. van der Wee, Eric Giltay, Martijn S. van Noorden, Serge A.R.B. Rombouts, Tobias H. Donner and Sander Nieuwenhuis
Journal of Neuroscience 27 July 2016, 36 (30) 7865-7876; DOI: https://doi.org/10.1523/JNEUROSCI.0744-16.2016
Ruud L. van den Brink
1Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands,
2Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands,
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Thomas Pfeffer
3Department of Neurophysiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany,
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Christopher M. Warren
1Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands,
2Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands,
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Peter R. Murphy
1Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands,
2Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands,
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Klodiana-Daphne Tona
1Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands,
2Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands,
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Nic J. A. van der Wee
2Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands,
4Department of Psychiatry and
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Eric Giltay
4Department of Psychiatry and
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Martijn S. van Noorden
4Department of Psychiatry and
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Serge A.R.B. Rombouts
1Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands,
2Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands,
5Department of Radiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands,
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Tobias H. Donner
3Department of Neurophysiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany,
6Department of Psychology, University of Amsterdam, 1012 WX, Amsterdam, The Netherlands, and
7Amsterdam Center for Brain and Cognition, Institute for Interdisciplinary Studies, 1001 NK Amsterdam, The Netherlands
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Sander Nieuwenhuis
1Institute of Psychology, Leiden University, 2333AK Leiden, The Netherlands,
2Leiden Institute for Brain and Cognition, 2333AK Leiden, The Netherlands,
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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.

SIGNIFICANCE STATEMENT 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.

  • catecholamines
  • functional connectivity
  • gain
  • neuromodulation
  • norepinephrine
  • resting-state fMRI
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The Journal of Neuroscience: 36 (30)
Journal of Neuroscience
Vol. 36, Issue 30
27 Jul 2016
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Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain
Ruud L. van den Brink, Thomas Pfeffer, Christopher M. Warren, Peter R. Murphy, Klodiana-Daphne Tona, Nic J. A. van der Wee, Eric Giltay, Martijn S. van Noorden, Serge A.R.B. Rombouts, Tobias H. Donner, Sander Nieuwenhuis
Journal of Neuroscience 27 July 2016, 36 (30) 7865-7876; DOI: 10.1523/JNEUROSCI.0744-16.2016

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Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain
Ruud L. van den Brink, Thomas Pfeffer, Christopher M. Warren, Peter R. Murphy, Klodiana-Daphne Tona, Nic J. A. van der Wee, Eric Giltay, Martijn S. van Noorden, Serge A.R.B. Rombouts, Tobias H. Donner, Sander Nieuwenhuis
Journal of Neuroscience 27 July 2016, 36 (30) 7865-7876; DOI: 10.1523/JNEUROSCI.0744-16.2016
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Keywords

  • catecholamines
  • functional connectivity
  • gain
  • neuromodulation
  • norepinephrine
  • resting-state fMRI

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