Where Is Itch Represented in the Brain, and How Does it Differ from Pain? An Activation Likelihood Estimation Meta-Analysis of Experimentally-Induced Itch
2019; Elsevier BV; Volume: 139; Issue: 10 Linguagem: Inglês
10.1016/j.jid.2019.04.007
ISSN1523-1747
AutoresCarl Roberts, Timo Giesbrecht, Andrej Stančák, Nicholas Fallon, Anna Thomas, Tim C. Kirkham,
Tópico(s)Olfactory and Sensory Function Studies
ResumoPerceptually, itch is clearly discernible from pain, yet both sensations exhibit a substantial anatomical overlap with common peripheral transmission and recruited brain regions. For example, recent functional magnetic resonance imaging (fMRI) studies have observed activations in the pain-processing network during cowhage- or histamine-induced itch in the thalamus (Leknes et al., 2007Leknes S.G. Bantick S. Willis C.M. Wilkinson J.D. Wise R.G. Tracey I. Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans.J Neurophysiol. 2007; 97: 415-422Crossref PubMed Scopus (123) Google Scholar, Mochizuki et al., 2009Mochizuki H. Inui K. Tanabe H.C. Akiyama L.F. Otsuru N. Yamashiro K. et al.Time course of activity in itch-related brain regions: a combined MEG–fMRI study.J Neurophysiol. 2009; 102: 2657-2666Crossref PubMed Scopus (63) Google Scholar, Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar, Valet et al., 2008Valet M. Pfab F. Sprenger T. Wöller A. Zimmer C. Behrendt H. et al.Cerebral processing of histamine-induced itch using short-term alternating temperature modulation–an FMRI study.J Invest Dermatol. 2008; 128: 426-433Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar), insular cortex (Herde et al., 2007Herde L. Forster C. Strupf M. Handwerker H.O. Itch induced by a novel method leads to limbic deactivations a functional MRI study.J Neurophysiol. 2007; 98: 2347-2356Crossref PubMed Scopus (82) Google Scholar, Leknes et al., 2007Leknes S.G. Bantick S. Willis C.M. Wilkinson J.D. Wise R.G. Tracey I. Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans.J Neurophysiol. 2007; 97: 415-422Crossref PubMed Scopus (123) Google Scholar), cingulate cortex (Mochizuki et al., 2007Mochizuki H. Sadato N. Saito D.N. Toyoda H. Tashiro M. Okamura N. et al.Neural correlates of perceptual difference between itching and pain: a human fMRI study.Neuroimage. 2007; 36: 706-717Crossref PubMed Scopus (94) Google Scholar), prefrontal cortex (Mochizuki et al., 2009Mochizuki H. Inui K. Tanabe H.C. Akiyama L.F. Otsuru N. Yamashiro K. et al.Time course of activity in itch-related brain regions: a combined MEG–fMRI study.J Neurophysiol. 2009; 102: 2657-2666Crossref PubMed Scopus (63) Google Scholar), postcentral gyrus (Herde et al., 2007Herde L. Forster C. Strupf M. Handwerker H.O. Itch induced by a novel method leads to limbic deactivations a functional MRI study.J Neurophysiol. 2007; 98: 2347-2356Crossref PubMed Scopus (82) Google Scholar, Ishiuji et al., 2009Ishiuji Y. Coghill R.C. Patel T.S. Oshiro Y. Kraft R.A. Yosipovitch G. Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis.Br J Dermatol. 2009; 161: 1072-1080Crossref PubMed Scopus (120) Google Scholar, Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar), parietal operculum (Mochizuki et al., 2009Mochizuki H. Inui K. Tanabe H.C. Akiyama L.F. Otsuru N. Yamashiro K. et al.Time course of activity in itch-related brain regions: a combined MEG–fMRI study.J Neurophysiol. 2009; 102: 2657-2666Crossref PubMed Scopus (63) Google Scholar, Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar), parahippocampal gyrus (Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar), and basal ganglia (Mochizuki et al., 2007Mochizuki H. Sadato N. Saito D.N. Toyoda H. Tashiro M. Okamura N. et al.Neural correlates of perceptual difference between itching and pain: a human fMRI study.Neuroimage. 2007; 36: 706-717Crossref PubMed Scopus (94) Google Scholar). However, the differences in brain processing of these two types of sensation have yet to be satisfactorily determined. The most significant advances in itch biology identifying itch-specific pathways have occurred in the peripheral nervous system, where there are itch-specific primary sensory neurons such as MrgprA3+ and NP2 (Dong and Dong, 2018Dong X. Dong X. Peripheral and central mechanisms of itch.Neuron. 2018; 98: 482-494Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar). However, interneurons (GRP+) that relay itch input to the spinal cord of the central nervous system also receive pain sensory information (Sun et al., 2017Sun S. Xu Q. Guo C. Guan Y. Liu Q. Dong X. Leaky gate model: intensity-dependent coding of pain and itch in the spinal cord.Neuron. 2017; 93: 840-853.e5Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Nevertheless, there are itch-specific GRPR+ interneurons in lamina I of the spinal cord, but projection neurons to the spinothalamic tract, thalamus, and beyond are polymodal (Hachisuka et al., 2016Hachisuka J. Baumbauer K.M. Omori Y. Snyder L.M. Koerber H.R. Ross S.E. Semi-intact ex vivo approach to investigate spinal somatosensory circuits.ELife. 2016; 5: e22866Crossref PubMed Scopus (3) Google Scholar), and thus decoding in the brain requires further exploration. To date, investigation of supraspinal processing of itch is limited and, as noted above, confined to a small number of imaging studies which show somatosensory, limbic, and motor-related activity similar to that evoked by noxious stimuli (for a detailed overview, see Lee et al., 2016Lee J.S. Han J.S. Lee K. Bang J. Lee H. The peripheral and central mechanisms underlying itch.BMB Rep. 2016; 49: 474-487Google Scholar). To contribute to our understanding of brain processing of itch compared with pain, we conducted activation likelihood estimation (ALE) meta-analysis of experimentally induced itch from the published fMRI literature and generated a comparison ALE map of experimental pain (using the previously reported coordinates of Tanasescu et al., 2016Tanasescu R. Cottam W.J. Condon L. Tench C.R. Auer D.P. Functional reorganisation in chronic pain and neural correlates of pain sensitisation: a coordinate based meta-analysis of 266 cutaneous pain fMRI studies.Neurosci Biobehav Rev. 2016; 68: 120-133Crossref PubMed Scopus (49) Google Scholar), to conduct meta-analytic conjunction/contrast analyses between the two sensations. Analyses were performed using Brainmap GingerALE, version 2.3.6 (Research Imaging Institute, San Antonio, TX). We adhered to the ALE method devised by Eickhoff et al., 2009Eickhoff S.B. Laird A.R. Grefkes C. Wang L.E. Zilles K. Fox P.T. Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: A random-effects approach based on empirical estimates of spatial uncertainty.Hum Brain Mapp. 2009; 30: 2907-2926Crossref PubMed Scopus (1303) Google Scholar, Eickhoff et al., 2012Eickhoff S.B. Bzdok D. Laird A.R. Kurth F. Fox P.T. Activation likelihood estimation meta-analysis revisited.Neuroimage. 2012; 59: 2349-2361Crossref PubMed Scopus (887) Google Scholar, with the correction devised by Turkeltaub et al., 2012Turkeltaub P.E. Eickhoff S.B. Laird A.R. Fox M. Wiener M. Fox P. Minimizing within-experiment and within-group effects in activation likelihood estimation meta-analyses.Hum Brain Mapp. 2012; 33: 1-13Crossref PubMed Scopus (731) Google Scholar. The P-values in our analyses were generated by 10,000 permutations. We used a cluster-level family-wise error correction at P < 0.05 to correct for multiple comparisons, following an initial cluster forming threshold of uncorrected P < 0.001 (see Supplementary Materials and Methods online for more information). ALE meta-analysis included all studies reporting whole brain fMRI analysis of experimentally induced itch (histamine, cowhage, or electrical stimulation). Data were pooled from a total of 11 experiments (from 10 papers, with a total of 117 participants and 313 reported foci) (Supplementary Figure S1). Significant clusters were observed in the thalamus, left frontal operculum cortex/insular cortex, and right frontal operculum cortex/insular cortex (Table 1, Figure 1).Table 1MNI Locations of Significant Clusters from the Itch ALE MapClusterBrain RegionPeak Voxel CoordinatesCluster Size (mm3)ALE Value (×10−2)No. of Contributing Experimentsxyzn%1Thalamus L-8-16103,9361.68763.640-1841.60-6-461.5710-421.36-8-14-21.31-10-18-81.202Frontal operculum / anterior insula / central operculum L-461222,0161.58545.45-3614-21.31-46281.25-54221.163Frontal operculum / anterior insula R401641,4241.72436.363810-21.33Abbreviations: ALE, activation likelihood estimation; L, left; MNI, Montreal Neurological Institute; R, rightCoordinates are reported in MNI space. Analysis used whole brain data from Herde et al., 2007Herde L. Forster C. Strupf M. Handwerker H.O. Itch induced by a novel method leads to limbic deactivations a functional MRI study.J Neurophysiol. 2007; 98: 2347-2356Crossref PubMed Scopus (82) Google Scholar, Ishiuji et al., 2009Ishiuji Y. Coghill R.C. Patel T.S. Oshiro Y. Kraft R.A. Yosipovitch G. Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis.Br J Dermatol. 2009; 161: 1072-1080Crossref PubMed Scopus (120) Google Scholar, Kleyn et al., 2012Kleyn C.E. McKie S. Ross A. Elliott R. Griffiths C.E. A temporal analysis of the central neural processing of itch.Br J Dermatol. 2012; 166: 994-1001Google Scholar, Leknes et al., 2007Leknes S.G. Bantick S. Willis C.M. Wilkinson J.D. Wise R.G. Tracey I. Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans.J Neurophysiol. 2007; 97: 415-422Crossref PubMed Scopus (123) Google Scholar, Mochizuki et al., 2007Mochizuki H. Sadato N. Saito D.N. Toyoda H. Tashiro M. Okamura N. et al.Neural correlates of perceptual difference between itching and pain: a human fMRI study.Neuroimage. 2007; 36: 706-717Crossref PubMed Scopus (94) Google Scholar, Mochizuki et al., 2009Mochizuki H. Inui K. Tanabe H.C. Akiyama L.F. Otsuru N. Yamashiro K. et al.Time course of activity in itch-related brain regions: a combined MEG–fMRI study.J Neurophysiol. 2009; 102: 2657-2666Crossref PubMed Scopus (63) Google Scholar, Mochizuki et al., 2014Mochizuki H. Tanaka S. Morita T. Wasaka T. Sadato N. Kakigi R. The cerebral representation of scratching-induced pleasantness.J Neurophysiol. 2014; 111: 488-498Crossref PubMed Scopus (49) Google Scholar, Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar, Valet et al., 2008Valet M. Pfab F. Sprenger T. Wöller A. Zimmer C. Behrendt H. et al.Cerebral processing of histamine-induced itch using short-term alternating temperature modulation–an FMRI study.J Invest Dermatol. 2008; 128: 426-433Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, and Walter et al., 2005Walter B. Sadlo M.N. Kupfer J. Niemeier V. Brosig B. Stark R. et al.Brain activation by histamine prick test-induced itch.J Invest Dermatol. 2005; 125: 380-382Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar. Studies that reported coordinates in the Talairach space were converted into MNI coordinates using GingerALE before analysis. Open table in a new tab Abbreviations: ALE, activation likelihood estimation; L, left; MNI, Montreal Neurological Institute; R, right Coordinates are reported in MNI space. Analysis used whole brain data from Herde et al., 2007Herde L. Forster C. Strupf M. Handwerker H.O. Itch induced by a novel method leads to limbic deactivations a functional MRI study.J Neurophysiol. 2007; 98: 2347-2356Crossref PubMed Scopus (82) Google Scholar, Ishiuji et al., 2009Ishiuji Y. Coghill R.C. Patel T.S. Oshiro Y. Kraft R.A. Yosipovitch G. Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis.Br J Dermatol. 2009; 161: 1072-1080Crossref PubMed Scopus (120) Google Scholar, Kleyn et al., 2012Kleyn C.E. McKie S. Ross A. Elliott R. Griffiths C.E. A temporal analysis of the central neural processing of itch.Br J Dermatol. 2012; 166: 994-1001Google Scholar, Leknes et al., 2007Leknes S.G. Bantick S. Willis C.M. Wilkinson J.D. Wise R.G. Tracey I. Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans.J Neurophysiol. 2007; 97: 415-422Crossref PubMed Scopus (123) Google Scholar, Mochizuki et al., 2007Mochizuki H. Sadato N. Saito D.N. Toyoda H. Tashiro M. Okamura N. et al.Neural correlates of perceptual difference between itching and pain: a human fMRI study.Neuroimage. 2007; 36: 706-717Crossref PubMed Scopus (94) Google Scholar, Mochizuki et al., 2009Mochizuki H. Inui K. Tanabe H.C. Akiyama L.F. Otsuru N. Yamashiro K. et al.Time course of activity in itch-related brain regions: a combined MEG–fMRI study.J Neurophysiol. 2009; 102: 2657-2666Crossref PubMed Scopus (63) Google Scholar, Mochizuki et al., 2014Mochizuki H. Tanaka S. Morita T. Wasaka T. Sadato N. Kakigi R. The cerebral representation of scratching-induced pleasantness.J Neurophysiol. 2014; 111: 488-498Crossref PubMed Scopus (49) Google Scholar, Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar, Valet et al., 2008Valet M. Pfab F. Sprenger T. Wöller A. Zimmer C. Behrendt H. et al.Cerebral processing of histamine-induced itch using short-term alternating temperature modulation–an FMRI study.J Invest Dermatol. 2008; 128: 426-433Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, and Walter et al., 2005Walter B. Sadlo M.N. Kupfer J. Niemeier V. Brosig B. Stark R. et al.Brain activation by histamine prick test-induced itch.J Invest Dermatol. 2005; 125: 380-382Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar. Studies that reported coordinates in the Talairach space were converted into MNI coordinates using GingerALE before analysis. Significant clusters resulting from experimental pain meta-analysis are fully described by Tanasescu et al., 2016Tanasescu R. Cottam W.J. Condon L. Tench C.R. Auer D.P. Functional reorganisation in chronic pain and neural correlates of pain sensitisation: a coordinate based meta-analysis of 266 cutaneous pain fMRI studies.Neurosci Biobehav Rev. 2016; 68: 120-133Crossref PubMed Scopus (49) Google Scholar; therefore, our ALE map of experimental pain was used only in the conjunction and contrast analysis described next. The conjunction analysis between itch and pain showed three significant clusters, located in the left thalamus and the left and right frontal operculum/insula. We chose a minimum cluster size of 500 mm3 for contrast analyses. For itch – pain, we identified five clusters: left and right thalamus, left anterior insula/frontal operculum, right central operculum, and right supramarginal gyrus. The reverse pain – itch contrast revealed four clusters: right parietal operculum/postcentral gyrus, right frontal pole (inferior frontal gyrus), left frontal pole (middle frontal gyrus), and right supramarginal gyrus. Experimental itch was associated with activations in the thalamus and anterior parts of the left and right insula/frontal operculum. There was a high degree of overlap in brain activation for itch and pain in the conjunction analysis. However, areas of the thalamus, anterior insula/frontal operculum, central operculum, and supramarginal gyrus showed significant differences in activation convergence in an itch – pain contrast. This finding suggests that somatosensory processing that is specific to itch resides in these areas, but further work is necessary to resolve this possibility with precision. Our meta-analysis confirms that the thalamus is the most consistently activated brain region in fMRI studies of experimental itch (Herde et al., 2007Herde L. Forster C. Strupf M. Handwerker H.O. Itch induced by a novel method leads to limbic deactivations a functional MRI study.J Neurophysiol. 2007; 98: 2347-2356Crossref PubMed Scopus (82) Google Scholar, Leknes et al., 2007Leknes S.G. Bantick S. Willis C.M. Wilkinson J.D. Wise R.G. Tracey I. Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans.J Neurophysiol. 2007; 97: 415-422Crossref PubMed Scopus (123) Google Scholar, Mochizuki et al., 2009Mochizuki H. Inui K. Tanabe H.C. Akiyama L.F. Otsuru N. Yamashiro K. et al.Time course of activity in itch-related brain regions: a combined MEG–fMRI study.J Neurophysiol. 2009; 102: 2657-2666Crossref PubMed Scopus (63) Google Scholar, Mochizuki et al., 2014Mochizuki H. Tanaka S. Morita T. Wasaka T. Sadato N. Kakigi R. The cerebral representation of scratching-induced pleasantness.J Neurophysiol. 2014; 111: 488-498Crossref PubMed Scopus (49) Google Scholar, Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar, Valet et al., 2008Valet M. Pfab F. Sprenger T. Wöller A. Zimmer C. Behrendt H. et al.Cerebral processing of histamine-induced itch using short-term alternating temperature modulation–an FMRI study.J Invest Dermatol. 2008; 128: 426-433Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar), and corroborates positron-emission tomography imaging studies that highlight the thalamus as important in the subjective appraisal of itch (Mochizuki et al., 2003Mochizuki H. Tashiro M. Kano M. Sakurada Y. Itoh M. Yanai K. Imaging of central itch modulation in the human brain using positron emission tomography.Pain. 2003; 105: 339-346Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). As with itch, the thalamus is acknowledged as a critical area involved in the perception of pain, being consistently reported in meta-analyses of fMRI studies on experimental pain (Jensen et al., 2016Jensen K.B. Regenbogen C. Ohse M.C. Frasnelli J. Freiherr J. Lundström J.N. Brain activations during pain: a neuroimaging meta-analysis of patients with pain and healthy controls.Pain. 2016; 157: 1279-1286Crossref PubMed Scopus (70) Google Scholar, Tanasescu et al., 2016Tanasescu R. Cottam W.J. Condon L. Tench C.R. Auer D.P. Functional reorganisation in chronic pain and neural correlates of pain sensitisation: a coordinate based meta-analysis of 266 cutaneous pain fMRI studies.Neurosci Biobehav Rev. 2016; 68: 120-133Crossref PubMed Scopus (49) Google Scholar). Our conjunction analysis showed substantial overlap between itch and pain in the thalamus, with every itch brain region overlapping with pain regions. However, areas of the left and right thalamus showed significant differences in convergence between itch and pain, supporting the proposals that variation in itch and pain perception can found in subregions of the thalamus (Drzezga et al., 2001Drzezga A. Darsow U. Treede R.D. Siebner H. Frisch M. Munz F. et al.Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies.Pain. 2001; 92: 295-305Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, Mochizuki et al., 2003Mochizuki H. Tashiro M. Kano M. Sakurada Y. Itoh M. Yanai K. Imaging of central itch modulation in the human brain using positron emission tomography.Pain. 2003; 105: 339-346Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), and that differences in thalamus sensitivity underlie the difference between the sensations (Mochizuki et al., 2007Mochizuki H. Sadato N. Saito D.N. Toyoda H. Tashiro M. Okamura N. et al.Neural correlates of perceptual difference between itching and pain: a human fMRI study.Neuroimage. 2007; 36: 706-717Crossref PubMed Scopus (94) Google Scholar). Clearly, convergence and divergence of thalamic activation in itch and pain are complex and require further investigation. The remaining two significant clusters from the itch ALE comprised bilateral activity in anterior parts of the insula and the frontal operculum area of the insula, confirming that these areas are consistently activated across studies of experimental itch (Herde et al., 2007Herde L. Forster C. Strupf M. Handwerker H.O. Itch induced by a novel method leads to limbic deactivations a functional MRI study.J Neurophysiol. 2007; 98: 2347-2356Crossref PubMed Scopus (82) Google Scholar, Leknes et al., 2007Leknes S.G. Bantick S. Willis C.M. Wilkinson J.D. Wise R.G. Tracey I. Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans.J Neurophysiol. 2007; 97: 415-422Crossref PubMed Scopus (123) Google Scholar, Mochizuki et al., 2009Mochizuki H. Inui K. Tanabe H.C. Akiyama L.F. Otsuru N. Yamashiro K. et al.Time course of activity in itch-related brain regions: a combined MEG–fMRI study.J Neurophysiol. 2009; 102: 2657-2666Crossref PubMed Scopus (63) Google Scholar, Mochizuki et al., 2014Mochizuki H. Tanaka S. Morita T. Wasaka T. Sadato N. Kakigi R. The cerebral representation of scratching-induced pleasantness.J Neurophysiol. 2014; 111: 488-498Crossref PubMed Scopus (49) Google Scholar, Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar). These areas are also commonly activated by pain (Yosipovitch and Mochizuki, 2015Yosipovitch G. Mochizuki H. Neuroimaging of itch as a tool of assessment of chronic itch and its management.Handb Exp Pharmacol. 2015; 226: 57-70Crossref Scopus (21) Google Scholar, Jensen et al., 2016Jensen K.B. Regenbogen C. Ohse M.C. Frasnelli J. Freiherr J. Lundström J.N. Brain activations during pain: a neuroimaging meta-analysis of patients with pain and healthy controls.Pain. 2016; 157: 1279-1286Crossref PubMed Scopus (70) Google Scholar, Tanasescu et al., 2016Tanasescu R. Cottam W.J. Condon L. Tench C.R. Auer D.P. Functional reorganisation in chronic pain and neural correlates of pain sensitisation: a coordinate based meta-analysis of 266 cutaneous pain fMRI studies.Neurosci Biobehav Rev. 2016; 68: 120-133Crossref PubMed Scopus (49) Google Scholar), and this was confirmed by our conjunction analysis. The insula is understood to process stimulus intensity in both pain and itch. For example, Papoiu et al., 2012Papoiu A.D. Coghill R.C. Kraft R.A. Wang H. Yosipovitch G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.Neuroimage. 2012; 59: 3611-3623Crossref PubMed Scopus (130) Google Scholar reported correlations between itch intensity and insula activity. Additionally, the anterior insula is associated with affective responses to stimuli, which may relate to the high rates of depression in atopic dermatitis (Gupta and Gupta, 1998Gupta M.A. Gupta A.K. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis.Br J Dermatol. 1998; 139: 846-850Crossref PubMed Scopus (709) Google Scholar). It is the affective component of itch which has led to the suggestion that psychological interventions, such as mindfulness or cognitive behavioral therapy, could prove successful in chronic itch treatment (Schut et al., 2014Schut C. Bosbach S. Gieler U. Kupfer J. Personality traits, depression and itch in patients with atopic dermatitis in an experimental setting: a regression analysis.Acta Derm Venereol. 2014; 94: 20-25Crossref PubMed Scopus (57) Google Scholar). Psychological interventions that reduce stress may produce positive effects on itch, as well as altering itch-associated brain activation, such as connectivity between the insular cortex and the anterior cingulate cortex (Mochizuki et al., 2017Mochizuki H. Schut C. Nattkemper L.A. Yosipovitch G. Brain mechanism of itch in atopic dermatitis and its possible alteration through non-invasive treatments.Allergol Int. 2017; 66: 14-21Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). The pain – itch subtraction showed residual activation in the parietal operculum and postcentral gyrus that seems to be specific to pain. Possibly, pain activates somatosensory cortices more reliably than itch, as is indicated by molecular imaging studies (Mochizuki et al., 2003Mochizuki H. Tashiro M. Kano M. Sakurada Y. Itoh M. Yanai K. Imaging of central itch modulation in the human brain using positron emission tomography.Pain. 2003; 105: 339-346Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, Darsow et al., 2000Darsow U. Drzezga A. Frisch M. Munz F. Weilke F. Bartenstein P. et al.Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions.J Invest Dermatol. 2000; 115: 1029-1033Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, Drzezga et al., 2001Drzezga A. Darsow U. Treede R.D. Siebner H. Frisch M. Munz F. et al.Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies.Pain. 2001; 92: 295-305Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). The main limitation of the present analyses is our focus on experimentally induced itch in healthy individuals. However, the strength of this approach is that confounding factors such as comorbidity are carefully controlled. It is probable that chronic and acute itch differ in central nervous system activity, and our findings therefore require validation with data from clinical populations. In addition, our analysis combined data from several different experimental itch methodologies. It may be that there are different types of itch, each with a distinct neural signature. The fundamental studies to explore this possibility have yet to be conducted, and the quantity of data on neural correlates of itch is currently insufficient to independently investigate specific types of itch with meta-analysis. We report that the thalamus and the affective areas of the anterior insula/frontal operculum are consistently activated across fMRI studies that induce itch experimentally. We propose these brain regions as targets for future exploratory neurofeedback experimentation. Data used in main analysis and supplementary analysis have been submitted with this manuscript as Supplementary Data online. These are available for replication, and building upon the current analysis. CAR, AS, NF, and TCK report grants from Unilever during the conduct of this study. TG and AT are employees of Unilever. This work was funded by Unilever. TG and AT are employees of Unilever, which markets personal care products including Dove DermaSeries. Conceptualization: CAR, TG; Formal Analysis: CAR; Funding Acquisition: TCK; Investigation: CAR; Methodology: CAR; Validation: NF; Writing - Original Draft Preparation: CAR; Writing - Review and Editing: CAR, TG, AS, NF, AT, TCK Systematic searches using three databases (MEDLINE, Scopus, and PsycINFO) were conducted using the following MeSH search terms: (fMRI AND [itch OR pruritus]) and (fMRI AND [affective touch OR pleasant touch]). Searches were restricted to terms found in the title or abstract of the articles. No date limit was set for the searches. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis method (Supplementary Table S2; http://www.prisma-statement.org). Generic inclusion criteria were the following: (i) human functional magnetic resonance imaging (fMRI) studies published up until February 2018; (ii) original articles reported in English; (iii) published in peer-reviewed journals; (iv) fMRI coordinates reported in the paper or supplementary material in either Montreal Neurological Institute (Evans et al., 1993Evans A.C. Collins D.L. Mills S.R. Brown E.D. Kelly R.L. Peters T.M. 3D statistical neuroanatomical models from 305 MRI volumes. In: Nuclear Science Symposium and Medical Imaging Conference, 1993 IEEE Conference Record..IEEE;. 1993; (p. 1813–7.)Google Scholar) or Talairach space (Talairach and Tournoux, 1988Talairach J. Tournoux P. Co-planar stereotaxic atlas of the human brain.3-Dimensional proportional system: an approach to cerebral imaging. Thieme, New York1988Google Scholar); (v) data were obtained from a healthy population (systemic disease-free); and (vi) analyses were conducted on whole brain fMRI data (region of interest analy
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