ABSTRACT Several brain regions have been implicated in human painful experiences, but none have been proven to be specific to pain. We exploited arterial spin-labeling quantitative perfusion

imaging and a newly developed procedure to identify a specific role for the dorsal posterior insula (dpIns) in pain. Tract tracing studies in animals identify a similar region as

fundamental to nociception, which suggests the dpIns is its human homolog and, as such, a potential therapeutic target. Access through your institution Buy or subscribe This is a preview of

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THALAMOCORTICAL NEURAL DYNAMICS ACROSS SPECIES Article 09 October 2023 METABOLITE ACTIVITY IN THE ANTERIOR CINGULATE CORTEX DURING A PAINFUL STIMULUS USING FUNCTIONAL MRS Article Open access

05 November 2020 INTRINSIC BRAIN CONNECTIVITY ALTERATIONS DESPITE INTACT PAIN INHIBITION IN SUBJECTS WITH NEUROPATHIC PAIN AFTER SPINAL CORD INJURY: A PILOT STUDY Article Open access 24

July 2023 CHANGE HISTORY * _ 26 MARCH 2015 In the version of this article initially published, the labels were reversed for the solid and dotted lines in Figure 2c. The error has been

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Eippert, K. Wiech and M. Chappell for their insights into the work. The research was funded by the Medical Research Council of Great Britain and Northern Ireland, the National Institute for

Health Research Oxford Biomedical Research Centre, the Wellcome Trust, and the Innovative Medicines Initiative joint undertaking, under grant agreement no 115007, resources of which are

composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA)

companies' in-kind contribution. AUTHOR INFORMATION Author notes * Andrew R Segerdahl and Melvin Mezue: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS *

Nuffield Department of Clinical Neuroscience, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), University of Oxford, Oxford, UK Andrew R Segerdahl, Melvin Mezue,

 Thomas W Okell & Irene Tracey * Nuffield Division of Anesthetics, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Andrew R Segerdahl, Melvin Mezue & 

Irene Tracey * Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA John T Farrar Authors * Andrew R

Segerdahl View author publications You can also search for this author inPubMed Google Scholar * Melvin Mezue View author publications You can also search for this author inPubMed Google

Scholar * Thomas W Okell View author publications You can also search for this author inPubMed Google Scholar * John T Farrar View author publications You can also search for this author

inPubMed Google Scholar * Irene Tracey View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors designed the study. A.R.S., M.M. and

J.T.F. collected the data. A.R.S. and M.M. analyzed the data. All authors interpreted the data. A.R.S., M.M. and I.T. wrote the manuscript. All authors contributed to the revisions.

CORRESPONDING AUTHOR Correspondence to Andrew R Segerdahl. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. INTEGRATED SUPPLEMENTARY INFORMATION

SUPPLEMENTARY FIGURE 1 INNOCUOUS, ONGOING VIBRATION INDUCED CBF CHANGES. a) Schematic of the vibration scan paradigm design that consisted of two identical multi-TI pCASL scans (parameters

identical to those described in the methods section). The baseline scan consisted of no vibration stimulation (grey); while the vibration scan (blue) consisted of a continuously oscillating

non-noxious stimulation of the subject’s foot for the duration of the 7min scan. To minimize habituation effects, the vibration stimulus frequency was oscillated between 1-2.0 Hz (fixed

amplitude of 1mA) using 0.5Hz step changes, at pseudorandom intervals between 20-60 seconds. Subjects were prompted to rate the stimulus intensity using a COVAS scale as discussed

previously. None of the subjects reported the vibration stimulation as painful (group mean pain intensity = 0). The group mean vibration saliency rating for the full vibration scan was 3.12

(s.e.m. =0.265). For clarity, a plot of vibration frequency over time is displayed in Figure (a) above. b) No significant correlation was observed between absolute CBF and either the ongoing

vibration intensity levels applied or with the ongoing perceived stimulus intensity levels reported by the subjects (Mixed Effects, z>2.3, p<0.05; cluster corrected; n=12). However,

sub-threshold activation clusters are visible within the contralateral medial operculum; a subsection of the "posterior insular and adjoining medial operculum" (PIMO) region that

Garcia-Larrea and others have highlighted as being linked to non-noxious sensory processing. For clarity, the non-significant sub-threshold clusters are shown in (b): red pixels represent

the absolute CBF increases correlated with the ongoing vibration stimulus intensity applied to the subject’s foot (i.e. stimulus frequency). Blue pixels represent the absolute CBF increases

correlated with the perceived stimulus intensity ratings reported by the subjects. The cluster in green represents the peak dpIns cluster that shows a strong positive correlation with

ongoing pain intensity reported in the current study. Statistical maps were overlaid on selected slices of the MNI brain. Radiological convention is used (L: left; R: right). SUPPLEMENTARY

FIGURE 2 PEAK PAIN PERIOD PERFUSION CHANGES. Absolute CBF changes during the 7-minute peak of the pain experience (peak pain period only vs baseline; Mixed Effects: z>2.3,p<0.05).

Statistical maps were overlaid on selected slices of the MNI brain. Radiological convention is used. Orange pixels represent supra-threshold absolute CBF increases while blue pixels

represent decreases. The anatomical locations for significant changes in CBF are listed in Supplementary table 2. These data highlight that the peak capsaicin pain relative to baseline is

linked to positive and negative perfusion changes in a select group of brain regions, some of which have been previously shown as involved in pain processing (ref. 5 and Baliki, M.N. et al.

Nat. Neurosci. 15, 1117–1119, 2012). Importantly, the region that shows maximal hyper-perfusion during the ‘peak pain’ compared to baseline is localized to the contralateral dpIns (mean CBF

change ± s.e.m; 15 ± 4.1% or 6.9 ± 1.9 ml / 100 g blood / min). This data supports the results from the regression analysis displayed in Figure 2; where the dpIns cluster reaches a peak of

activity at the time point of maximum capsaicin-induced pain. Importantly, none of the other regions identified here show a significant correlation with the ongoing pain ratings, as we found

was the case for the dpIns, even with a less strict statistical threshold. Radiological convention is used. L, left; R, right; dpIns, dorsal posterior insula; Ant. Ins, anterior insula;

NAc, nucleus accumbens; PCC, posterior cingulate. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1 and 2 and Supplementary Tables 1 and 2 (PDF 3281 kb) RIGHTS

AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Segerdahl, A., Mezue, M., Okell, T. _et al._ The dorsal posterior insula subserves a fundamental role in human

pain. _Nat Neurosci_ 18, 499–500 (2015). https://doi.org/10.1038/nn.3969 Download citation * Received: 16 October 2014 * Accepted: 06 February 2015 * Published: 09 March 2015 * Issue Date:

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