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Cited by 11Pain Mechanisms and TreatmentsMultiple Sclerosis Research StudiesPain Management and Treatment

Coupling cognitive and brainstem dysfunction in multiple sclerosis-related chronic neuropathic limb pain

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Foley, Peter, Kong, Yazhuo, Dirvanskiene, Ramune, valdes-Hernandez, Maria, Bastiani, Matteo, Murnane, Jonathan, Sellar, Robin, Roberts, Neil +7 more·2022·Brain Communications
DOI 10.1093/braincomms/fcac124PMC PMC9155950
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Abstract

Chronic pain in multiple sclerosis is common and difficult to treat. Its mechanisms remain incompletely understood. Dysfunction of the descending pain modulatory system is known to contribute to human chronic pain conditions. However, it is not clear how alterations in executive function influence this network, despite healthy volunteer studies linking function of the descending pain modulatory system, to cognition. In adults with multiple sclerosis-associated chronic neuropathic limb pain, compared to those without pain, we hypothesized altered functional connectivity of the descending pain modulatory system, coupled to executive dysfunction. Specifically we hypothesized reduced mental flexibility, because of potential importance in stimulus reappraisal. To investigate these hypotheses, we conducted a case-control cross-sectional study of 47 adults with relapsing remitting multiple sclerosis (31 with chronic neuropathic limb pain, 16 without pain), employing clinical, neuropsychological, structural, and functional MRI measures. We measured brain lesions and atrophy affecting descending pain modulatory system structures. Both cognitive and affective dysfunctions were confirmed in the chronic neuropathic limb pain group, including reduced mental flexibility (Delis Kaplan Executive Function System card sorting tests P < 0.001). Functional connectivity of rostral anterior cingulate and ventrolateral periaqueductal gray, key structures of the descending pain modulatory system, was significantly lower in the group experiencing chronic neuropathic pain. There was no significant between-group difference in whole-brain grey matter or lesion volumes, nor lesion volume affecting white matter tracts between rostral anterior cingulate and periaqueductal gray. Brainstem-specific lesion volume was higher in the chronic neuropathic limb pain group (P = 0.0017). Differential functional connectivity remained after correction for brainstem-specific lesion volume. Gabapentinoid medications were more frequently used in the chronic pain group. We describe executive dysfunction in people with multiple sclerosis affected by chronic neuropathic pain, along with functional and structural MRI evidence compatible with dysfunction of the descending pain modulatory system. These findings extend understanding of close inter-relationships between cognition, function of the descending pain modulatory system, and chronic pain, both in multiple sclerosis and more generally in human chronic pain conditions. These findings could support application of pharmacological and cognitive interventions in chronic neuropathic pain associated with multiple sclerosis.

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  • The discrepancy between the previous review's 26.8% and the current review's 22.3% may be due to the previous review's inclusion of studies that exclusively investigated people with multiple sclerosis and pain, likely overinflating estimates.

    “This discrepancy may be due to their inclusion of studies that exclusively investigated pwMS with pain, likely overinflating estimates (Ata et al. 2021; Foley et al. 2022; Khan and Pallant 2007; Kim et al. 2019, 2020; Solaro et al. 2004; Srotova et al. 2021; Young et al. 2017).”

    From The Prevalence of Neuropathic Pain in Multiple Sclerosis—A Systematic Review and Meta‐Analysis Using the <scp>NeuPSIG</scp> Algorithm (2026) · cites this paper as Foley et al. 2022

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Cited by

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Authors
Foley, P., Kong, Y., Dirvanskiene, R., valdes-Hernandez, M., Bastiani, M., Murnane, J., Sellar, R., Roberts, N., Pernet, C., Weir, C., Bak, T., Colvin, L., Chandran, S., Fallon, M., & Tracey, I.
Affiliations
  • University of Edinburgh (GB)
  • Chinese Academy of Sciences (CN)
  • Dementia Research Institute, University of Edinburgh , Edinburgh, UK
  • University of Nottingham (GB)
  • University of Dundee (GB)
  • John Radcliffe Hospital (GB)
Corresponding author
Foley, Peter
ORCID
Venue
Brain Communications
Publisher
Oxford University Press (OUP)
Published
2022-05-02
Volume
4
Issue
3
Pages
fcac124-fcac124
ISSN
2632-1297 (ISSN-L)
DOI
10.1093/braincomms/fcac124
PMC
PMC9155950
OpenAlex
W4280614322
Cited by
11
References
4
Citations by year
2026: 3 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 1
FWCI
1.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • a Rowling Scholar fellowship
  • University of Edinburgh
  • Medical Research Council of Great Britain and Northern Ireland and Wellcome
  • University of Oxford
  • National Health Service Lothian via the Edinburgh Clinical Trials Unit
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
Keywords
multiple sclerosis, chronic neuropathic pain, executive dysfunction, cognitive flexibility, functional connectivity, rostral anterior cingulate cortex, ventrolateral periaqueductal gray, brainstem lesions, brainstem atrophy, gabapentinoids

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