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Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration

Hsieh, Paul-Chena,b; Tseng, Ming-Tsungc; Chao, Chi-Chaod; Lin, Yea-Hueyd; Tseng, Wen-Yih I.e,f; Liu, Kuan-Hongb; Chiang, Ming-Changb,*; Hsieh, Sung-Tsangd,g

doi: 10.1097/j.pain.0000000000000128
Research Paper

Small-fiber neuropathy (SFN) is hallmarked by degeneration of small unmyelinated peripheral nerve fibers in the skin. Traditionally, it has been considered as a pure disorder of the peripheral nervous system. Nevertheless, previous work found that dysfunction of skin nerves led to abnormal recruitment of pain-related regions, suggesting that the brain may be affected in SFN. This report combined structural and functional magnetic resonance imaging to identify structural and functional changes in the brain of 19 patients with SFN compared with 17 healthy controls. We applied tensor-based morphometry to detect brain structural alterations in SFN. Greater volume reduction in pain-processing regions, particularly the bilateral anterior cingulate cortices (ACCs), was associated with greater depletion of intraepidermal nerve fibers, a pathological biomarker of skin nerve degeneration. Based on the hypothesis that structural alterations in the pain-processing regions might impair their functional connectivity, we further applied psychophysiological interaction analysis to assess functional connectivity of the ACCs during noxious heat stimulation. There was significant reduction in functional connectivity from the ACCs to the limbic areas (the parahippocampal gyrus and the posterior cingulate cortex), pain-processing area (the insula), and visuospatial areas (the cuneus). Moreover, the degree of reduction in functional connectivity for the ACC to the amygdala and the precuneus was linearly correlated with the severity of intraepidermal nerve fiber depletion. Our findings suggest that SFN is not a pure peripheral nervous system disorder. The pain-related brain networks tend to break into functionally independent components, with severity linked to the degree of skin nerve degeneration.

Supplemental Digital Content is Available in the Text.Functional connectivity of pain-processing, limbic, and cognitive-related regions was reduced in small-fiber neuropathy, with severity linked to skin nerve degeneration.

aDepartment of Medicine, National Taiwan University, Taipei, Taiwan

bDepartment of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan

cGraduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan

Departments of dNeurology and

eMedical Imaging, National Taiwan University Hospital, Taipei, Taiwan

fCenter for Optoelectronic Biomedicine, National Taiwan University College of Medicine, Taipei, Taiwan

gDepartment of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan

Corresponding author. Address: Department of Biomedical Engineering, National Yang-Ming University, No. 155, Sec. 2, Linong St, Taipei 112, Taiwan. Tel.: (886)-2-2826-7110; fax: (886)-2-2821-0847. E-mail address: (M.-C. Chiang).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received September 23, 2014

Received in revised form January 12, 2015

Accepted February 03, 2015

© 2015 International Association for the Study of Pain
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