Painful stimulation increases functional connectivity between supplementary motor area and thalamus in patients with small fibre neuropathy

European Journal of Pain, vol. 29, pp. e4720

Abstract

BACKGROUND: The lead symptom of small fibre neuropathy (SFN) is neuropathic pain. Recent functional magnetic resonance imaging (fMRI) studies have indicated central changes in SFN patients of different etiologies. However, less is known about brain functional connectivity during acute pain processing in idiopathic SFN. METHODS: We conducted fMRI with thermal heat pain application (left volar forearm) in 32 idiopathic SFN patients and 31 healthy controls. We performed functional connectivity analyses with right supplementary motor area (SMA), left insula, and left caudate nucleus (CN) as seed regions, respectively. Since pathogenic gain-of-function variants in voltage gated sodium channels (Nav) have been linked to SFN pathophysiology, explorative connectivity analyses were performed in a homogenous subsample of patients carrying rare heterozygous missense variants. RESULTS: For right SMA, we found significantly higher connectivity with the right thalamus in SFN patients compared to controls. This connectivity correlated significantly with intraepidermal nerve fibre density, suggesting a link between peripheral and central pain processing. We found significantly reduced connections between right SMA and right middle frontal gyrus in patients with Nav variants. Likewise, connectivity between left CN and right frontal pole was decreased. CONCLUSIONS: Aberrant functional connectivity in SFN is in line with previous research on other chronic pain syndromes. Functional connectivity changes may be linked to SFN, highlighting the need to determine if they result from peripheral changes causing abnormal somatosensory processing. This understanding may be crucial for assessing their impact on painful symptoms and therapy response. SIGNIFICANCE STATEMENT: We found increased functional connectivity between SMA and thalamus during painful stimulation in patients with idiopathic SFN. Connectivity correlated significantly with intraepidermal nerve fibre density, suggesting a link between peripheral and central pain processing. Our findings emphasize the importance of investigating functional connectivity changes as a potential feature of SFN.

Authors 12

1. Sebastian Scheliga corresponding Aachen Department of Psychiatry, Psychotherapy and Psychosomatics Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty RWTH Aachen University Aachen Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

2. Maike Franziska Dohrn Aachen Department of Neurology, Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Neurology, Medical Faculty RWTH Aachen University Aachen Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

3. Thilo Kellermann Aachen Department of Psychiatry, Psychotherapy and Psychosomatics Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Forschungszentrum Jülich · Universitätsklinikum Aachen · Jülich Aachen Research Alliance · RWTH Aachen University

   Affiliation as printed

   Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty RWTH Aachen University Aachen Germany

   Institute of Neuroscience and Medicine: JARA‐Institute Brain Structure Function Relationship (INM 10) Research Center Jülich, Wilhelm‐Johnen‐Straβe Jülich Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

4. Angelika Lampert Aachen Institute of Neurophysiology, Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Neurophysiology, Medical Faculty RWTH Aachen University Aachen Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Institute of Neurophysiology, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

5. Roman Rolke Aachen Department of Palliative Medicine Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Palliative Medicine, Medical Faculty RWTH Aachen University Aachen Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Department of Palliative Medicine, Medical Faculty RWTH, Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

6. Barbara Namer Aachen Institute of Neurophysiology, Medical Faculty Research group Neuroscience Interdisciplinary Center for Clinical Research (IZKF) Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Neurophysiology, Medical Faculty RWTH Aachen University Aachen Germany

   Research Group Neuroscience, Interdisciplinary Centre for Clinical Research, Medical Faculty RWTH Aachen University Aachen Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Institute of Neurophysiology, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Research Group Neuroscience, Interdisciplinary Centre for Clinical Research, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

7. Greta Z. Peschke Aachen Department of Neurology, Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Neurology, Medical Faculty RWTH Aachen University Aachen Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

8. Nortje van den Braak Aachen Department of Neurology, Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Neurology, Medical Faculty RWTH Aachen University Aachen Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

9. Annette Lischka Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty Scientific Center for Neuropathic Pain Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty RWTH Aachen University Aachen Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany

   Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

10. Marc Spehr Aachen Department of Chemosensation Scientific Center for Neuropathic Pain Aachen

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Chemosensation RWTH Aachen University, Institute for Biology II Aachen Germany

    Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

    Department of Chemosensation, RWTH Aachen University, Institute for Biology II, Aachen, Germany

    Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

11. Han‐Gue Jo Aachen Scientific Center for Neuropathic Pain Aachen

    Kunsan National University · Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    School of Computer Science & Engineering Kunsan National University Gunsan Republic of Korea

    Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

    School of Computer Science & Engineering Kunsan National University Gunsan Republic of Korea

    Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany

12. Ute Habel Aachen Department of Psychiatry, Psychotherapy and Psychosomatics Medical Faculty Scientific Center for Neuropathic Pain Aachen

    Forschungszentrum Jülich · Universitätsklinikum Aachen · Jülich Aachen Research Alliance · RWTH Aachen University

    Affiliation as printed

    Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty RWTH Aachen University Aachen Germany

    Institute of Neuroscience and Medicine: JARA‐Institute Brain Structure Function Relationship (INM 10) Research Center Jülich, Wilhelm‐Johnen‐Straβe Jülich Germany

    Scientific Center for Neuropathic Pain Aachen, SCNAachen Uniklinik RWTH Aachen University Aachen Germany

    Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty, RWTH Aachen University, Aachen, Germany

    Scientific Center for Neuropathic Pain Aachen, SCNAachen, Uniklinik RWTH Aachen University, Aachen, Germany