Imagine that you are cooking, your food in the oven is ready and you want to take it out. Hunger makes you impatient and you put your bare hand into the oven, but you accidentally touch the hot surface. You get a painful burn. The area of the burn becomes and remains more sensitive for a while. If you were to touch or apply a sharp object on that area you would feel increased piercing pain, i.e. primary hyperalgesia (hyperalgesia in the lesioned area). Interestingly, you would also experience that this increased piercing pain can be evoked by stimulation of the surrounding non-injured skin, i.e. secondary hyperalgesia (hyperalgesia in a non-lesioned area). Secondary hyperalgesia can be explained by a process that amplifies the responses at a more ‘central’ level. The phenomenon related to secondary hyperalgesia is called ‘central sensitization’ and it has great relevance in the pain field. It is believed that this increased response contributes to protecting the body from further damage and promoting healing, but it can also contribute to pain persisting beyond the healing phase (chronic pain).
Central sensitization can be induced experimentally in healthy volunteers. It is reversible and constitutes a very useful model to characterize the consequences of intense nociceptor activation. There are several models for inducing central sensitization in humans. One of these, High Frequency Stimulation (HFS) of the skin, has been used extensively by our group (van den Broeke et al., 2010, van den Broeke et al., 2011, van den Broeke et al., 2012, van den Broeke and Mouraux, 2014, Van Den Broeke and Mouraux, 2014) and presents several advantages as a design with which to answer our research questions. HFS consists of brief but intense trains of electrical stimuli applied at a given body location. The homologue body area is used as a control. HFS does not lead to ongoing sensations, meaning that the moment the stimuli stop, the pain also stops. This allows us to study the effects of nociceptor sensitization without the ‘confounding’ effect of ongoing pain or discomfort.
Previous studies have demonstrated that HFS induces a long-lasting enhancement of the perception and electroencephalographic (EEG) brain responses to sharp mechanical stimuli applied to the sensitized arm (Klein et al., 2004, Pfau et al., 2011, van den Broeke et al., 2016). These findings show that central sensitization induced by HFS is associated with increased responsiveness of the nociceptive system (Ikeda et al., 2003).
However, nociception is not the only sense that can provide relevant information about the presence of a threat to the body. Vision can also inform us about imminent contact of the injured limb with objects in the external world. For this reason, if the aim of sensitization is to protect the limb from further injury and promote healing, one might also expect that, after inducing sensitization, the processing of visual stimuli projected onto the sensitized limb might also be changed.
To test this hypothesis, we explored whether EEG brain responses to visual stimuli were enhanced when these stimuli were projected onto the sensitized arm as compared to when they were projected onto the control, non-sensitized, arm (Torta et al., 2017). The obtained data confirmed our hypothesis: visual stimuli projected onto the sensitized arm elicited enhanced brain responses as compared to stimuli projected onto the control arm. Interestingly, in contrast to our previous findings (van den Broeke et al., 2016), the enhanced brain responses were observed at the first post measurement (20 minutes after HFS) but were no longer present at a second post measurement at (45 minutes after HFS). Increased sensitivity to mechanical sharp stimuli, instead, persisted for at least 45 minutes.
We propose two main take home messages: First, that after inducing central sensitization experimentally the processing of both nociceptive and non-nociceptive stimuli is modulated. Second, that the effects on sharp mechanical stimuli and visual stimuli have different time courses, suggesting that they rely on different mechanisms. Current studies are trying to elucidate what these short and long mechanisms are.
About Diana Torta
Diana Torta is post-doctoral fellow at the Faculty of Psychology and Educational Sciences at KU Leuven (Leuven) and Chargé de Recherche at the Institute of Neuroscience, UCL (Brussels). Her research aims at characterizing the effects of cognition on pain and sensitization, and the mechanisms underlying crossmodal interactions between pain and other sensory modalities.
She is funded by an Asthenes long-term structural funding Methusalem grant by the Flemish-Government investing the transition from acute to chronic bodily symptoms (KU Leuven) and by personal grants from the Fund for Scientific Research of the French speaking community of Belgium (F.R.S.-FNRS) and the E-G-G Efic Grunenthal award.
Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J. Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science. 2003;299(5610):1237-40.
Klein T, Magerl W, Hopf HC, Sandkuhler J, Treede RD. Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004;24(4):964-71.
Pfau DB, Klein T, Putzer D, Pogatzki-Zahn EM, Treede RD, Magerl W. Analysis of hyperalgesia time courses in humans after painful electrical high-frequency stimulation identifies a possible transition from early to late LTP-like pain plasticity. Pain. 2011;152(7):1532-9.
Torta DM, Van Den Broeke EN, Filbrich L, Jacob B, Lambert J, Mouraux A. Intense pain influences the cortical processing of visual stimuli projected onto the sensitized skin. Pain. 2017;158(4):691-7.
van den Broeke EN, Lambert J, Huang G, Mouraux A. Central Sensitization of Mechanical Nociceptive Pathways Is Associated with a Long-Lasting Increase of Pinprick-Evoked Brain Potentials. Frontiers in human neuroscience. 2016;10:531.
van den Broeke EN, Mouraux A. Enhanced brain responses to C-fiber input in the area of secondary hyperalgesia induced by high-frequency electrical stimulation of the skin. Journal of neurophysiology. 2014;112(9):2059-66.
Van Den Broeke EN, Mouraux A. High frequency electrical stimulation of human skin induces heterotopical mechanical and heat hyperalgesia and enhanced responses to vibrotactile input. Journal of neurophysiology. 2014.
van den Broeke EN, van Heck CH, Ceelen LA, van Rijn CM, van Goor H, Wilder-Smith OH. The effect of high-frequency conditioning stimulation of human skin on reported pain intensity and event-related potentials. Journal of neurophysiology. 2012;108(8):2276-81.
van den Broeke EN, van Heck CH, van Rijn CM, Wilder-Smith OH. Neural correlates of heterotopic facilitation induced after high frequency electrical stimulation of nociceptive pathways. Molecular pain. 2011;7:28.
van den Broeke EN, van Rijn CM, Biurrun Manresa JA, Andersen OK, Arendt-Nielsen L, Wilder-Smith OH. Neurophysiological correlates of nociceptive heterosynaptic long-term potentiation in humans. Journal of neurophysiology. 2010;103(4):2107-13.