Poster No:
2508
Submission Type:
Abstract Submission
Authors:
Sebastian Scheliga1, Han-Gue Jo2, Maike F. Dohrn3, Thilo Kellermann4, Angelika Lampert5, Roman Rolke6, Annette Lischka7, Greta Peschke3, Nortje Van den Braak3, Ute Habel8
Institutions:
1RWTH Aachen University Hospital, Aachen, North Rhine-Westphalia, 2Kunsan National University, Gunsan, Jeollabuk-do, 3Department of Neurology, Medical Faculty RWTH Aachen University, Aachen, North Rhine-Westphalia, 4Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty RWTH Aachen University, Aachen, North Rhine-Westphalia, 5Institute of Neurophysiology, Medical Faculty RWTH Aachen University, Aachen, North Rhine-Westphalia, 6Department of Palliative Medicine, Medical Faculty RWTH Aachen University, Aachen, North Rhine-Westphalia, 7Institute for Human Genetics and Genomic Medicine, Medical Faculty RWTH Aachen University, Aachen, North Rhine-Westphalia, 8Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University Hospital, Aachen, North Rhine-Westphalia
First Author:
Co-Author(s):
Han-Gue Jo
Kunsan National University
Gunsan, Jeollabuk-do
Maike F. Dohrn
Department of Neurology, Medical Faculty RWTH Aachen University
Aachen, North Rhine-Westphalia
Thilo Kellermann
Department of Psychiatry, Psychotherapy and Psychosomatics, Medical Faculty RWTH Aachen University
Aachen, North Rhine-Westphalia
Angelika Lampert
Institute of Neurophysiology, Medical Faculty RWTH Aachen University
Aachen, North Rhine-Westphalia
Roman Rolke
Department of Palliative Medicine, Medical Faculty RWTH Aachen University
Aachen, North Rhine-Westphalia
Annette Lischka
Institute for Human Genetics and Genomic Medicine, Medical Faculty RWTH Aachen University
Aachen, North Rhine-Westphalia
Greta Peschke
Department of Neurology, Medical Faculty RWTH Aachen University
Aachen, North Rhine-Westphalia
Nortje Van den Braak
Department of Neurology, Medical Faculty RWTH Aachen University
Aachen, North Rhine-Westphalia
Ute Habel
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University Hospital
Aachen, North Rhine-Westphalia
Introduction:
Small fiber neuropathy (SFN) is clinically characterized by neuropathic pain and autonomic complaints1. Traditionally, SFN has been considered as a peripheral nervous system disorder. However, studies found aberrant brain functional connectivity during resting state (RS) in SFN patients2. Such functional changes were observed in neuropathic pain patients with different etiologies, e.g. diabetes mellitus3. To date, knowledge about RS alterations in idiopathic SFN is still lacking. Therefore, we used RS-fMRI to assess functional connectivity in a patient sample with idiopathic SFN. Gain-of-function mutations in voltage-gated sodium channels (Nav) have been discussed to play a role in the pathophysiology of SFN4. Therefore, we further analyzed RS connectivity in a homogenous subsample of SFN patients carrying missense Nav variants.
Methods:
We recruited 31 healthy controls and 32 SFN patients. Patients with known neuropathy etiologies were excluded. In the patient sample, nine individuals carried rare heterozygous missense variants in SCN9A (n = 3), SCN10A (n = 3), or SCN11A (n = 4). One subject carried variants in SCN9A and SCN10A, respectively. We used seed-based voxel analysis; a whole-brain connectivity approach implemented in CONN toolbox, to compare RS connectivity between patients and controls. We defined right caudate nucleus as seed region for each analysis because we found reduced gray matter volume of that region in a previous voxel-based morphometry study from our lab5. We cluster-level threshold of p < 0.05 (FWE corrected). All regions showing significant group differences were considered for correlation analysis. Thereby, we extracted the respective connectivity coefficient and correlated it with total pain score from painDETECT questionnaire6. We used Pearson's correlation analysis implemented in SPSS 27. Finally, we calculated explorative seed-based analyses to compare the patient subsample carrying Nav variants with healthy controls and with patients without known genetic variants.
Results:
Comparing SFN patients and controls, seed to voxel analysis revealed significantly reduced connectivity between right caudate nucleus seed and left supplementary motor area (SMA) in SFN patients. For the left caudate seed, there were no significant group differences. Moreover, comparing patients with missense variants and controls, explorative analysis yielded increased connectivity between right caudate seed and right Crus2 in Nav variant carriers compared with controls. Further, we compared patients without variants and healthy subjects. We identified increased connectivity between right caudate and left ACC for the patients. In controls, we found increased connectivity with bilateral SMA. There were no significant differences comparing patients with and without missense variants. We performed correlation analysis across all SFN patients. Here, we found a significant negative correlation between caudate-SMA connectivity and pain score (r = -.364, p = 0.044).
Conclusions:
We found reduced RS connectivity between caudate nucleus and SMA in patients with SFN. These functional changes may point to deficits in the regulation of pain. Deficient RS connectivity may represent a disruption of endogenous pain modulatory systems elicited by long-term nociceptive input7. Further, the negative correlation between caudate-SMA connectivity and pain score suggests that lower RS connectivity may be linked with higher pain perception in SFN. Interestingly, we found higher connectivity between caudate nucleus and Crus2 in SFN patients with missense Nav variants compared with controls. Due to regulation deficits, increased connectivity may reflect compensatory functioning within endogenous pain-modulation networks8 especially pronounced in patients with Nav variants. Future studies on SFN patients should further assess the involvement of sodium channel mutations in pain processing and the resulting brain functional changes.
Modeling and Analysis Methods:
Task-Independent and Resting-State Analysis 2
Perception, Attention and Motor Behavior:
Perception: Pain and Visceral 1
Keywords:
FUNCTIONAL MRI
MRI
Pain
Peripheral Nerve
Other - Resting State fMRI, Connectivity, Small-Fiber Neuropathy
1|2Indicates the priority used for review
Provide references using author date format
1. Sopacua, M., Hoeijmakers, J. G., Merkies, I. S., Lauria, G., Waxman, S. G., & Faber, C. G. (2019). Small‐fiber neuropathy: expanding the clinical pain universe. Journal of the Peripheral Nervous System, 24(1), 19-33.
2. Chao, C. C., Tseng, M. T., Lin, Y. H., Hsieh, P. C., Lin, C. H. J., Huang, S. L., ... & Chiang, M. C. (2021). Brain imaging signature of neuropathic pain phenotypes in small-fiber neuropathy: Altered thalamic connectome and its associations with skin nerve degeneration. Pain, 162(5), 1387-1399.
3. Zhang, Q., Zhang, P., Yan, R., Xu, X., Mao, C., Liu, X., ... & Wu, J. (2019). A single-blinded trial using resting-state functional magnetic resonance imaging of brain activity in patients with type 2 diabetes and painful neuropathy. Diabetes Therapy, 10, 135-147.
4. Lampert, A., Eberhardt, M., & Waxman, S. G. (2014). Altered sodium channel gating as molecular basis for pain: contribution of activation, inactivation, and resurgent currents. Voltage Gated Sodium Channels, 91-110.
5. Scheliga, S., Dohrn, M. F., Habel, U., Lampert, A., Rolke, R., Lischka, A., Van den Braak, N., Spehr, M., Jo, H. G., & Kellermann, T. Reduced gray matter volume and cortical thickness in patients with Small-Fiber Neuropathy (under review).
6. Freynhagen, R., Baron, R., Gockel, U., & Tölle, T. R. (2006). Pain DETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Current medical research and opinion, 22(10), 1911-1920.
7. Bushnell, M. C., Čeko, M., & Low, L. A. (2013). Cognitive and emotional control of pain and its disruption in chronic pain. Nature Reviews Neuroscience, 14(7), 502-511.
8. Mills, E. P., Di Pietro, F., Alshelh, Z., Peck, C. C., Murray, G. M., Vickers, E. R., & Henderson, L. A. (2018). Brainstem pain-control circuitry connectivity in chronic neuropathic pain. Journal of Neuroscience, 38(2), 465-473.