Tamasauskas, Arnas, Perini, Irene, Minde, Jan, Keller, Simon S 
ORCID: 0000-0001-5247-9795, Fallon, Nicholas ORCID: 0000-0003-1451-6983, Frank, Bernhard ORCID: 0000-0001-5405-4942, Morrison, India and Marshall, Andrew ORCID: 0000-0001-8273-7089
(2026)
White matter differences in motor and affective-motivational networks of pain-indifferent carriers of the R221W mutation
NEUROBIOLOGY OF PAIN, 20.
100211-.
ISSN 2452-073X, 2452-073X
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1-s2.0-S2452073X26000048-main.pdf - Open Access published version Download (4MB) | Preview |
Abstract
The R221W mutation on the nerve growth factor gene results in reduced peripheral C-nociceptor density and behavioural indifference to painful stimuli. While functional neuroimaging has revealed altered cortical and sub-cortical pain processing in R221W carriers, structural white matter changes remain unexplored and may suggest an anatomical basis of symptoms. Heterozygous R221W carriers’ (n = 11) and matched controls’ (n = 11) diffusion MRI data were compared using fixel-based analysis, and complimentary edge and node analyses using graph theory and network-based statistics. Whole-brain and region of interest (ROI) fixel-based analyses revealed significantly reduced fibre density and fibre-bundle cross-section in brainstem motor tracts of R221W carriers, encompassing the corticospinal pathways, corona radiata, external capsule, cerebellar peduncles, and pontine crossing (p ' 0.05). Graph theory analysis of pain-processing ROIs demonstrated significantly reduced node degree and betweenness centrality in the Left Anterior Cingulate Cortex (ACC) of R221W carriers, indicating structural isolation of this affective-motivational hub. Network-based statistics identified significantly stronger connectivity between the Right Thalamus and Right ACC in R221W carriers, in contrast to weaker connectivity connecting the Right Thalamus to the Left ACC and Left Insula (p ' 0.05). These findings indicate potentially reduced brainstem motor tract integrity and altered cortical network topology, specifically the structural isolation of the Left ACC. This, alongside potentially compensatory right-sided thalamo-cortical connectivity and preserved sensory afferent pathways, supports a model of R221W pain indifference as motor under-reactivity rather than sensory insensitivity.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Congenital pain insensitivity, Neuropathy, Genetic conditon, Fixel analysis, Graphtheory, Network based statistics, Diffusion tensor imaging, White matter integrity, Region of interest analysis, Nociceptive network, Saliance network |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences > Inst. Life Courses & Medical Sciences Faculty of Health & Life Sciences > Inst. Population Health Faculty of Health & Life Sciences > Inst. Population Health > Psychology Faculty of Health & Life Sciences > Inst. Population Health > Inst. Population Health (T&R Staff) Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology (T&R Staff) Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Pharmacology & Therapeutics |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 02 Apr 2026 13:19 |
| Last Modified: | 23 May 2026 11:14 |
| DOI: | 10.1016/j.ynpai.2026.100211 |
| Open Access URL: | https://www.sciencedirect.com/science/article/pii/... |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3197821 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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