Brain imaging signatures of the relationship between epidermal nerve fibers and heat pain perception.
Although the small-diameter primary afferent fibers in the skin promptly respond to nociceptive stimuli and convey sensory inputs to the central nervous system, the neural signatures that underpin the relationship between cutaneous afferent fibers and pain perception remain elusive. We combined skin biopsy at the lateral aspect of the distal leg, which is used to quantify cutaneous afferent fibers, with fMRI, which is used to assess brain responses and functional connectivity, to investigate the relationship between cutaneous sensory nerves and the corresponding pain perception in the brain after applying heat pain stimulation to the dorsum of the right foot in healthy subjects. During painful stimulation, the degree of cutaneous innervation, as measured by epidermal nerve fiber density, was correlated with individual blood oxygen level-dependent (BOLD) signals of the posterior insular cortex and of the thalamus, periaqueductal gray, and rostral ventromedial medulla. Pain perception was associated with the activation of the anterior insular cortex and with the functional connectivity from the anterior insular cortex to the primary somatosensory cortex during painful stimulation. Most importantly, both epidermal nerve fiber density and activity in the posterior insular cortex showed a positive correlation with the strength of coupling under pain between the anterior insular cortex and the primary somatosensory cortex. Thus, our findings support the notion that the neural circuitry subserving pain perception interacts with the cerebral correlates of peripheral nociceptive fibers, which implicates an indirect role for skin nerves in human pain perception.
Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: mingtsungtseng@ntu.edu.tw.
Ming-Tsung
MT
Tseng
Oxford Center for Functional Magnetic Resonance Imaging of the Brain and Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
Yazhuo
Y
Kong
Department of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan.
Ming-Chang
MC
Chiang
Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
Chi-Chao
CC
Chao
Center for Optoelectronic Biomedicine, National Taiwan University Hospital, Taipei, Taiwan.
Wen-Yih I
WY
Tseng
Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan; Department of Anatomy and Cell Biology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address: shsieh@ntu.edu.tw.
Sung-Tsang
ST
Hsieh
D000328:Adult; D000368:Aged; D001921:Brain / Q000502:physiology*; D001931:Brain Mapping; D004817:Epidermis / Q000294:innervation*; D005260:Female; D006358:Hot Temperature; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059225:Nociception / Q000502:physiology*; D009619:Nociceptors / Q000166:cytology*; D010812:Physical Stimulation
Contact heat-evoked potential; Functional magnetic resonance imaging (fMRI); Heat; Pain; Psychophysical interaction analysis; Skin innervation