European Journal of Applied Physiology

, Volume 118, Issue 5, pp 971–978 | Cite as

Cutaneous neural activity and endothelial involvement in cold-induced vasodilatation

  • Gary J. Hodges
  • Matthew M. Mallette
  • Stephen S. Cheung
Original Article


Whether sympathetic withdrawal or endothelial dilators such as nitric oxide (NO) contributes to cold-induced vasodilation (CIVD) events is unclear. We measured blood flow and finger skin temperature (Tfinger) of the index finger in nine participants during hand immersion in a water bath at 35 °C for 30 min, then at 8 °C for 30 min. Data were binned into 10 s averages for the entire 60 min protocol for laser-Doppler flux (LDF) and Tfinger. At baseline, Tfinger was 35.3 ± 0.2 °C and LDF was 227 ± 28 PU. During hand cooling, minimum Tfinger was 10.9 ± 0.4 °C and LDF was 15 ± 4 PU. All participants exhibited at least one CIVD event (Tfinger increase ≥ 1 °C), with a mean peak Tfinger 13.2 ± 0.8 °C and a corresponding peak LDF of 116 ± 34 PU. A Morlet mother wavelet was then used to perform wavelet analysis on the LDF signal, with frequency ranges of 0.005–0.01 Hz (endothelial NO-independent), 0.01–0.02 Hz (endothelial NO-dependent), and 0.02–0.05 Hz (neurogenic). The synchronicity of wavelet fluctuations with rising LDF coincident with CIVD events was then quantified using Auto-regressive Integrated Moving Average time-series analysis. Fluctuations in neural activity were strongly synchronized in real time with increasing LDF (stationary-r2 = 0.73 and Ljung-box statistic > 0.05), while endothelial activities were only moderately synchronized (NO-independent r2 = 0.15, > 0.05; NO dependent r2 = 0.16, > 0.05). We conclude that there is a direct, real-time correlation of LDF responses with neural activity but not endothelial-mediated mechanisms. Importantly, it seems that neural activity is consistently reduced prior to CIVD, suggesting that sympathetic withdrawal directly contributes to CIVD onset.


Auto-regressive integrated moving average Time-series analysis Finger blood flow Cold injury Wavelet analysis Sympathetic nervous system 



Analysis of variance


Auto-regressive integrated moving average


Arbitrary units


Cold-induced vasodilatation


Laser-Doppler flux


Perfusion units


Finger temperature

\({\overline {T} _{{\text{sk}}}}\)

Mean skin temperature



We thank the participants for volunteering their time and effort. We thank Desmond G. Stewart, Paul J. Davison, and Steven A.H. Ferguson for assistance with data collection.

Author contributions

GJH conceived the experiments. GJH, MMM, and SSC designed the experiments. GJH collected the data. GJH and MMM reduced and analysed the data. GJH, MMM, and SSC interpreted the data. GJH drafted the manuscript. MMM and SSC revised the manuscript critically for intellectual content. All authors approved the final version of the manuscript.


The study was funded by a Natural Science and Engineering Research Council—Discovery Grant (SSC, #227912-12), and SSC was supported by a Canada Research Chair.


  1. Bailey SR, Eid AH, Mitra S, Flavahan S, Flavahan NA (2004) Rho kinase mediates cold-induced constriction of cutaneous arteries: role of alpha2C-adrenoceptor translocation. Circ Res 94(10):1367–1374. CrossRefPubMedGoogle Scholar
  2. Bailey SR, Mitra S, Flavahan S, Flavahan NA (2005) Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol 289(1):H243–250. CrossRefPubMedGoogle Scholar
  3. Binti Md Isa K, Kawasaki N, Ueyama K, Sumii T, Kudo S (2011) Effects of cold exposure and shear stress on endothelial nitric oxide synthase activation. Biochem Biophys Res Commun 412(2):318–322. CrossRefPubMedGoogle Scholar
  4. Bracic M, Stefanovska A (1998) Wavelet-based analysis of human blood-flow dynamics. Bull Math Biol 60(5):919–935. CrossRefPubMedGoogle Scholar
  5. Cheung SS, Daanen HA (2012) Dynamic adaptation of the peripheral circulation to cold exposure. Microcirculation 19(1):65–77. CrossRefPubMedGoogle Scholar
  6. Ekenvall L, Lindblad LE, Norbeck O, Etzell BM (1988) Alpha-adrenoceptors and cold-induced vasoconstriction in human finger skin. Am J Physiol 255(5 Pt 2):H1000–1003PubMedGoogle Scholar
  7. Felicijan A, Golja P, Milcinski M, Cheung SS, Mekjavic IB (2008) Enhancement of cold-induced vasodilatation following acclimatization to altitude. Eur J Appl Physiol 104(2):201–206. CrossRefPubMedGoogle Scholar
  8. Flavahan NA, Lindblad LE, Verbeuren TJ, Shepherd JT, Vanhoutte PM (1985) Cooling and alpha 1- and alpha 2-adrenergic responses in cutaneous veins: role of receptor reserve. Am J Physiol 249(5 Pt 2):H950–955PubMedGoogle Scholar
  9. Flouris AD, Cheung SS (2009) Influence of thermal balance on cold-induced vasodilation. J Appl Physiol (1985) 106(4):1264–1271. CrossRefGoogle Scholar
  10. Flouris AD, Cheung SS (2010) On the origins of cold-induced vasodilation. Eur J Appl Physiol 108(6):1281–1282. CrossRefPubMedGoogle Scholar
  11. Flouris AD, Westwood DA, Mekjavic IB, Cheung SS (2008) Effect of body temperature on cold induced vasodilation. Eur J Appl Physiol 104(3):491–499. CrossRefPubMedGoogle Scholar
  12. Hodges GJ, Johnson JM (2009) Adrenergic control of the human cutaneous circulation. Appl Physiol Nutr Metab 34(5):829–839. CrossRefPubMedGoogle Scholar
  13. Hodges GJ, Zhao K, Kosiba WA, Johnson JM (2006) The involvement of nitric oxide in the cutaneous vasoconstrictor response to local cooling in humans. J Physiol 574(Pt 3):849–857. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Hodges GJ, Kosiba WA, Zhao K, Johnson JM (2009) The involvement of heating rate and vasoconstrictor nerves in the cutaneous vasodilator response to skin warming. Am J Physiol Heart Circ Physiol 296(1):H51–56. CrossRefPubMedGoogle Scholar
  15. Hodges GJ, Mallette MM, Martin ZT, Del Pozzi AT (2017a) Effect of sympathetic nerve blockade on low-frequency oscillations of forearm and leg skin blood flow in healthy humans. Microcirculation. CrossRefPubMedGoogle Scholar
  16. Hodges GJ, Mallette MM, Tew GA, Saxton JM, Moss J, Ruddock AD, Klonizakis M (2017b) Effect of age on cutaneous vasomotor responses during local skin heating. Microvasc Res 112:47–52. CrossRefPubMedGoogle Scholar
  17. Iatsenko D, McClintock PV, Stefanovska A (2013) Linear and synchrosqueezed time-frequency representations revisited. Part I: Overview, standards of use, related issues and algorithms. arXiv:1310.7215v2 [math.NA]
  18. Iatsenko D, McClintock PV, Stefanovska A (2015) Linear and synchrosqueezed time–frequency representations revisited: overview, standards of use, resolution, reconstruction, concentration, and algorithms. Digit Signal Proc 42:1–26CrossRefGoogle Scholar
  19. Iatsenko D, McClintock PV, Stefanovska A (2016) Extraction of instantaneous frequencies from ridges in time–frequency representations of signals. Sig Process 125:290–303CrossRefGoogle Scholar
  20. Johnson JM (1990) The cutaneous circulation. Laser-Doppler blood flowmetry. Kluwer Academic Publishers, BostonGoogle Scholar
  21. Johnson JM, Kellogg DL Jr (2010) Local thermal control of the human cutaneous circulation. J Appl Physiol 109(4):1229–1238. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Johnson JM, Minson CT, Kellogg DL Jr (2014) Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation. Compr Physiol 4(1):33–89. CrossRefPubMedGoogle Scholar
  23. Kellogg DL Jr, Johnson JM, Kosiba WA (1989) Selective abolition of adrenergic vasoconstrictor responses in skin by local iontophoresis of bretylium. Am J Physiol 257(5 Pt 2):H1599–1606PubMedGoogle Scholar
  24. Kvandal P, Stefanovska A, Veber M, Kvernmo HD, Kirkeboen KA (2003) Regulation of human cutaneous circulation evaluated by laser Doppler flowmetry, iontophoresis, and spectral analysis: importance of nitric oxide and prostaglandines. Microvasc Res 65(3):160–171CrossRefPubMedGoogle Scholar
  25. Kvandal P, Landsverk SA, Bernjak A, Stefanovska A, Kvernmo HD, Kirkeboen KA (2006) Low-frequency oscillations of the laser Doppler perfusion signal in human skin. Microvasc Res 72(3):120–127CrossRefPubMedGoogle Scholar
  26. Kvernmo HD, Stefanovska A, Kirkeboen KA, Kvernmo K (1999) Oscillations in the human cutaneous blood perfusion signal modified by endothelium-dependent and endothelium-independent vasodilators. Microvasc Res 57(3):289–309CrossRefGoogle Scholar
  27. Lewis T (1930) Observations upon the reactions of the vessels of the human skin to cold. Heart 15:177–208Google Scholar
  28. Lindblad LE, Ekenvall L (1986) Alpha-adrenoceptors in the vessels of human finger skin. Acta Physiol Scand 128(2):219–222CrossRefPubMedGoogle Scholar
  29. Lindblad LE, Ekenvall L, Klingstedt C (1990) Neural regulation of vascular tone and cold induced vasoconstriction in human finger skin. J Auton Nerv Syst 30(2):169–173CrossRefPubMedGoogle Scholar
  30. Mallette MM, Hodges GJ, McGarr GW, Gabriel DA, Cheung SS (2017) Spectral analysis of reflex cutaneous vasodilatation during passive heat stress. Microvasc Res 111:42–48. CrossRefPubMedGoogle Scholar
  31. Öberg PA (1990) Laser-Doppler flowmetry. Crit Rev Biomed Eng 18:125–163PubMedGoogle Scholar
  32. Ramanathan NL (1964) A new weighting system for mean sufrace temperature of the human body. J Appl Physiol 19:531–533CrossRefPubMedPubMedCentralGoogle Scholar
  33. Saumet JL, Kellogg DL Jr, Taylor WF, Johnson JM (1988) Cutaneous laser-Doppler flowmetry: influence of underlying muscle blood flow. J Appl Physiol 65(1):478–481CrossRefPubMedGoogle Scholar
  34. Sessler DI (2009) Thermoregulatory defense mechanisms. Crit Care Med 37(7 Suppl):S203–210. CrossRefPubMedGoogle Scholar
  35. Soderstrom T, Stefanovska A, Veber M, Svensson H (2003) Involvement of sympathetic nerve activity in skin blood flow oscillations in humans. Am J Physiol Heart Circ Physiol 284(5):H1638–1646. CrossRefPubMedGoogle Scholar
  36. Stefanovska A, Bracic M, Kvernmo HD (1999) Wavelet analysis of oscillations in the peripheral blood circulation measured by laser Doppler technique. IEEE Trans Biomed Eng 46(10):1230–1239CrossRefPubMedGoogle Scholar
  37. Stensrud T, Stang J, Thorsen E, Braten V (2016) Exhaled nitric oxide concentration in the period of 60 min after submaximal exercise in the cold. Clin Physiol Funct Imaging 36(2):85–91. CrossRefPubMedGoogle Scholar
  38. Therminarias A, Oddou MF, Favre-Juvin A, Flore P, Delaire M (1998) Bronchial obstruction and exhaled nitric oxide response during exercise in cold air. Eur Respir J 12(5):1040–1045CrossRefPubMedGoogle Scholar
  39. Thompson-Torgerson CS, Holowatz LA, Flavahan NA, Kenney WL (2007) Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin. Am J Physiol Heart Circ Physiol 292(4):H1700–1705. CrossRefPubMedGoogle Scholar
  40. Vanhoutte PM (ed) (1980) Physical factors of regulation, vol II. Handbook of physiology. American Physiological Society, Bethesda, MDGoogle Scholar
  41. Vanhoutte PM, Shepherd JT (1970) Effect of cooling on beta-receptor mechanisms in isolated cutaneous veins of the dog. Microvasc Res 2(4):454–461CrossRefPubMedGoogle Scholar
  42. Vanhoutte PM, Verbeuren TJ (1976a) Depression by local cooling of 3H-norepinephrine release evoked by nerve stimulation in cutaneous veins. Blood Vessels 13(1–2):92–99PubMedGoogle Scholar
  43. Vanhoutte PM, Verbeuren TJ (1976b) Inhibition by acetylcholine of 3H-norepinephrine release in cutaneous veins after alpha-adrenergic blockade. Arch Int Pharmacodyn Ther 221(2):344–346PubMedGoogle Scholar
  44. Vanhoutte PM, Cooke JP, Lindblad LE, Shepherd JT, Flavahan NA (1985) Modulation of postjunctional alpha-adrenergic responsiveness by local changes in temperature. Clin Sci (Lond) 68(Suppl 10):121s–123sCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Environmental Ergonomics Laboratory, Department of KinesiologyBrock UniversitySt. CatharinesCanada

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