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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.00899

Early pain exposure influences functional brain connectivity in very preterm neonates

 Domenico Tortora1*,  Mariasavina Severino1,  Carlo Di Biase2,  Mariya Malova2, Alessandro Parodi2, Diego Minghetti2, Cristina Traggiai2,  Sara Uccella3, Luca Boeri3, Giovanni Morana1, Andrea Rossi1* and  Luca A. Ramenghi2
  • 1Neuroradiology Unit, Giannina Gaslini Institute (IRCCS), Italy
  • 2Neonatal Intensive Care Unit, Giannina Gaslini Institute (IRCCS), Italy
  • 3Child Neuropsychiatry Unit, Giannina Gaslini Institute (IRCCS), Italy

Background
Early exposure to nociceptive events may cause brain structural alterations in preterm neonates (PN), with long-lasting consequences on neurodevelopmental outcome. Little is known on the extent to which early pain may affect brain connectivity. We aim to evaluate brain functional connectivity changes in PN that underwent multiple invasive procedures during the postnatal period, and to correlate them with the neurodevelopmental outcome at 24 months.
Methods
In this prospective case-control study, we collected information about exposure to painful events during the early postnatal period and resting-state BOLD-fMRI data at term equivalent age from two groups of PN: 33 subjected to painful procedures during the neonatal intensive care (mean gestational age 26.9±1.8 weeks) and 13 who did not require invasive procedures (average gestational age 31.2±2.1 weeks). A data-driven principal-component-based multivariate pattern analysis (MVPA) was used to investigate the effect of early pain exposure on brain functional connectivity, and the relationship between connectivity changes and neurodevelopmental outcome at 24 months, assessed with Griffiths’Developmental Scale-Revised:0-2.
Results
Early pain was associated with decreased functional connectivity between thalami and bilateral somatosensory cortex, and between the right insular cortex and ipsilateral amygdala and hippocampal regions, with a more evident effect in PN undergoing more invasive procedures. Functional connectivity of the right thalamocortical pathway was related to neuromotor outcome at 24 months (P=.003).
Conclusions
Early exposure to pain is associated with abnormal functional connectivity of developing networks involved in the modulation of noxious stimuli in PN, contributing to the neurodevelopmental consequence of preterm birth.

Keywords: Preterm neonatal brain, fMRI, Pain, Functional Connectivity, neonatal neuroimaging, nociceceptive modulation, brain connectitvity, resting state

Received: 14 Apr 2019; Accepted: 12 Aug 2019.

Edited by:

Alessandra Griffa, VU University Amsterdam, Netherlands

Reviewed by:

Chiara Nosarti, King's College London, United Kingdom
Ruth E. Grunau, University of British Columbia, Canada
Lynne J. Williams, BC Children's Hospital MRI Research Facility, Canada
Lorenzo Fabrizi, University College London, United Kingdom  

Copyright: © 2019 Tortora, Severino, Di Biase, Malova, Parodi, Minghetti, Traggiai, Uccella, Boeri, Morana, Rossi and Ramenghi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Domenico Tortora, Giannina Gaslini Institute (IRCCS), Neuroradiology Unit, Genoa, Italy, domenicotortora@gaslini.org
Dr. Andrea Rossi, Giannina Gaslini Institute (IRCCS), Neuroradiology Unit, Genoa, Italy, andrearossi@gaslini.org