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Altered Brainstem Pain-Modulation Circuitry Connectivity During Spontaneous Pain Intensity Fluctuations

Authors Mills EP, Alshelh Z, Kosanovic D, Di Pietro F, Vickers ER, Macey PM, Henderson LA

Received 5 March 2020

Accepted for publication 7 July 2020

Published 4 September 2020 Volume 2020:13 Pages 2223—2235


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Michael Schatman

Emily P Mills,1 Zeynab Alshelh,1 Danny Kosanovic,1 Flavia Di Pietro,1 E Russell Vickers,1 Paul M Macey,2 Luke A Henderson1

1Department of Anatomy and Histology, University of Sydney, Sydney, NSW 2006, Australia; 2School of Nursing and Brain Research Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

Correspondence: Luke A Henderson
Department of Anatomy and Histology, F13, University of Sydney, Sydney, NSW, Australia
Tel +612 9351 7063
Fax +612 9351 6556

Background: Chronic pain, particularly that following nerve injury, can occur in the absence of external stimuli. Although the ongoing pain is sometimes continuous, in many individuals the intensity of their pain fluctuates. Experimental animal studies have shown that the brainstem contains circuits that modulate nociceptive information at the primary afferent synapse and these circuits are involved in maintaining ongoing continuous neuropathic pain. However, it remains unknown if these circuits are involved in regulating fluctuations of ongoing neuropathic pain in humans.
Methods: We used functional magnetic resonance imaging to determine whether in 19 subjects with painful trigeminal neuropathy, brainstem pain-modulation circuitry function changes according to moment-to-moment fluctuations in spontaneous pain intensity as rated online over a 12-minute period.
Results: We found that when pain intensity was spontaneously high, connectivity strengths between regions of the brainstem endogenous pain-modulating circuitry—the midbrain periaqueductal gray, rostral ventromedial medulla (RVM), and the spinal trigeminal nucleus (SpV)—were high, and vice-versa (when pain was low, connectivity was low). Additionally, sliding-window connectivity analysis using 50-second windows revealed a significant positive relationship between ongoing pain intensity and RVM-SpV connectivity over the duration of the 12-minute scan.
Conclusion: These data reveal that moment-to-moment changes in brainstem pain-modulation circuitry functioning likely contribute to fluctuations in spontaneous pain intensity in individuals with chronic neuropathic pain.

Keywords: midbrain periaqueductal gray matter, rostral ventromedial medulla, spinal trigeminal nucleus, dynamic connectivity, functional connectivity, spontaneous pain

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