The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey

Elena Makovac; Alessandra Venezia; David Hohenschurz-Schmidt; Ottavia Dipasquale; Jade B. Jackson; Sonia Medina; Owen O'Daly; Steve C.R. Williams; Stephen B. McMahon; Matthew A. Howard

doi:10.1113/JP282013

The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey

Elena Makovac^*, Alessandra Venezia, David Hohenschurz-Schmidt, Ottavia Dipasquale, Jade B. Jackson, Sonia Medina, Owen O'Daly, Steve C.R. Williams, Stephen B. McMahon, Matthew A. Howard

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

Abstract: There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure + cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of the LF-HRVnu-CPM association. CPM response magnitude was also negatively correlated with vmPFC GM volume. Our multi-modal approach, using behavioural, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments. (Figure presented.). Key points: Heart rate variability (HRV) is associated with descending pain modulation as measured by the conditioned pain modulation protocol (CPM). There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro-medial prefrontal cortex (vmPFC). CPM scores are also associated with vmPFC grey matter volume. The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM. Our data provide new evidence of interactions between the autonomic nervous system and descending pain mechanisms.

Original language	English
Pages (from-to)	5243-5260
Number of pages	18
Journal	Journal of Physiology
Volume	599
Issue number	23
Early online date	8 Nov 2021
DOIs	https://doi.org/10.1113/JP282013
Publication status	Published - 1 Dec 2021

Keywords

descending pain modulation
heart rate variability
periaqueductal grey
resting state
voxel-based morphometry

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10.1113/JP282013

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@article{2b7ba2ae5b3049648b3e1dbe18b0aae9,

title = "The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey",

abstract = "Abstract: There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between {\textquoteleft}pressure-only{\textquoteright} and {\textquoteleft}pressure + cold{\textquoteright} stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of the LF-HRVnu-CPM association. CPM response magnitude was also negatively correlated with vmPFC GM volume. Our multi-modal approach, using behavioural, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments. (Figure presented.). Key points: Heart rate variability (HRV) is associated with descending pain modulation as measured by the conditioned pain modulation protocol (CPM). There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro-medial prefrontal cortex (vmPFC). CPM scores are also associated with vmPFC grey matter volume. The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM. Our data provide new evidence of interactions between the autonomic nervous system and descending pain mechanisms.",

keywords = "descending pain modulation, heart rate variability, periaqueductal grey, resting state, voxel-based morphometry",

author = "Elena Makovac and Alessandra Venezia and David Hohenschurz-Schmidt and Ottavia Dipasquale and Jackson, {Jade B.} and Sonia Medina and Owen O'Daly and Williams, {Steve C.R.} and McMahon, {Stephen B.} and Howard, {Matthew A.}",

note = "Funding Information: This work was funded by a Medical Research Council Experimental Medicine Challenge Grant (MR/N026969/1). M.A.H., S.M. and S.W. are also supported by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Trust. E.M. is also supported by an EFIC-Gr?nenthal-Grant. The authors also wish to thank the Wellcome Trust for their ongoing support of our neuroimaging research and Simon Hill for both the development and calibration of the stimulation equipment and Giovanni Calcagnini for his input on heart rate variability analysis. Funding Information: This work was funded by a Medical Research Council Experimental Medicine Challenge Grant (MR/N026969/1). M.A.H., S.M. and S.W. are also supported by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Trust. E.M. is also supported by an EFIC‐Gr{\"u}nenthal‐Grant. Publisher Copyright: {\textcopyright} 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society",

year = "2021",

month = dec,

day = "1",

doi = "10.1113/JP282013",

language = "English",

volume = "599",

pages = "5243--5260",

journal = "Journal of Physiology",

issn = "0022-3751",

publisher = "Wiley",

number = "23",

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TY - JOUR

T1 - The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey

AU - Makovac, Elena

AU - Venezia, Alessandra

AU - Hohenschurz-Schmidt, David

AU - Dipasquale, Ottavia

AU - Jackson, Jade B.

AU - Medina, Sonia

AU - O'Daly, Owen

AU - Williams, Steve C.R.

AU - McMahon, Stephen B.

AU - Howard, Matthew A.

N1 - Funding Information: This work was funded by a Medical Research Council Experimental Medicine Challenge Grant (MR/N026969/1). M.A.H., S.M. and S.W. are also supported by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Trust. E.M. is also supported by an EFIC-Gr?nenthal-Grant. The authors also wish to thank the Wellcome Trust for their ongoing support of our neuroimaging research and Simon Hill for both the development and calibration of the stimulation equipment and Giovanni Calcagnini for his input on heart rate variability analysis. Funding Information: This work was funded by a Medical Research Council Experimental Medicine Challenge Grant (MR/N026969/1). M.A.H., S.M. and S.W. are also supported by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Trust. E.M. is also supported by an EFIC‐Grünenthal‐Grant. Publisher Copyright: © 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Abstract: There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure + cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of the LF-HRVnu-CPM association. CPM response magnitude was also negatively correlated with vmPFC GM volume. Our multi-modal approach, using behavioural, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments. (Figure presented.). Key points: Heart rate variability (HRV) is associated with descending pain modulation as measured by the conditioned pain modulation protocol (CPM). There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro-medial prefrontal cortex (vmPFC). CPM scores are also associated with vmPFC grey matter volume. The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM. Our data provide new evidence of interactions between the autonomic nervous system and descending pain mechanisms.

AB - Abstract: There is a strict interaction between the autonomic nervous system (ANS) and pain, which might involve descending pain modulatory mechanisms. The periaqueductal grey (PAG) is involved both in descending pain modulation and ANS, but its role in mediating this relationship has not yet been explored. Here, we sought to determine brain regions mediating ANS and descending pain control associations. Thirty participants underwent conditioned pain modulation (CPM) assessments, in which they rated painful pressure stimuli applied to their thumbnail, either alone or with a painful cold contralateral stimulation. Differences in pain ratings between ‘pressure-only’ and ‘pressure + cold’ stimuli provided a measure of descending pain control. In 18 of the 30 participants, structural scans and two functional MRI assessments, one pain-free and one during cold-pain were acquired. Heart rate variability (HRV) was simultaneously recorded. Normalised low-frequency HRV (LF-HRVnu) and the CPM score were negatively correlated; individuals with higher LF-HRVnu during pain reported reductions in pain during CPM. PAG-ventro-medial prefrontal cortex (vmPFC) and PAG-rostral ventromedial medulla (RVM) functional connectivity correlated negatively with the CPM. Importantly, PAG-vmPFC functional connectivity mediated the strength of the LF-HRVnu-CPM association. CPM response magnitude was also negatively correlated with vmPFC GM volume. Our multi-modal approach, using behavioural, physiological and MRI measures, provides important new evidence of interactions between ANS and descending pain mechanisms. ANS dysregulation and dysfunctional descending pain modulation are characteristics of chronic pain. We suggest that further investigation of body-brain interactions in chronic pain patients may catalyse the development of new treatments. (Figure presented.). Key points: Heart rate variability (HRV) is associated with descending pain modulation as measured by the conditioned pain modulation protocol (CPM). There is an association between CPM scores and the functional connectivity between the periaqueductal grey (PAG) and ventro-medial prefrontal cortex (vmPFC). CPM scores are also associated with vmPFC grey matter volume. The strength of functional connectivity between the PAG and vmPFC mediates the association between HRV and CPM. Our data provide new evidence of interactions between the autonomic nervous system and descending pain mechanisms.

KW - descending pain modulation

KW - heart rate variability

KW - periaqueductal grey

KW - resting state

KW - voxel-based morphometry

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JO - Journal of Physiology

JF - Journal of Physiology

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ER -

The association between pain-induced autonomic reactivity and descending pain control is mediated by the periaqueductal grey

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Keywords

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