Role of Operculoinsular Cortices in Human Pain Processing: Converging Evidence from PET, fMRI, Dipole Modeling, and Intracerebral Recordings of Evoked Potentials

doi:10.1006/nimg.2002.1315

NeuroImage

Volume 17, Issue 3, November 2002, Pages 1336-1346

https://doi.org/10.1006/nimg.2002.1315 Get rights and content

Abstract

Insular and SII cortices have been consistently shown by PET, fMRI, EPs, and MEG techniques to be activated bilaterally by a nociceptive stimulation. The aim of the present study was to refer to, and to compare within a common stereotactic space, the nociceptive responses obtained in humans by (i) PET, (ii) fMRI, (iii) dipole modeling of scalp LEPs, and (iv) intracerebral recordings of LEPs. PET, fMRI, and scalp LEPs were obtained from normal subjects during thermal pain. Operculoinsular LEPs were obtained from 13 patients using deep brain electrodes implanted for presurgical evaluation of drug-resistant epilepsy. Whatever the technique, we obtained responses which were located bilaterally in the insular and SII cortices. In electrophysiological responses (LEPs) the SII insular contribution peaked between 150 and 250 ms poststimulus and corresponded to the earliest portions of the whole cerebral response. Group analysis of PET and fMRI data showed highly consistent responses contralateral to stimulation. On single-subject analysis, LEPs and fMRI activations were concentrated in relatively restricted volumes even though spatial sampling was quite different for both techniques. Despite our multimodal approach, however, it was not possible to separate insular from SII activities. Individual variations in the anatomy and function of SII and insular cortices may explain this limitation. This multimodal study provides, however, cross-validated spatial and temporal information on the pain-related processes occurring in the operculoinsular region, which thus appears as a major site for the early cortical pain encoding in the human brain.

References (63)

J.R. Augustine
Circuitry and functional aspects of the insular lobe in primates including humans
Brain Res. Rev.
(1996)
B. Bromm et al.
Brain electrical source analysis of laser evoked potentials in response to painful trigeminal nerve stimulation
Electroencephalogr. Clin. Neurophysiol.
(1995)
J.C. Brooks et al.
fMRI of thermal pain: Effects of stimulus laterality and attention
NeuroImage
(2002)
S.W. Derbyshire et al.
Pain processing during three levels of noxious stimulation produces differential patterns of central activity
Pain
(1997)
M. Frot et al.
Operculo-insular responses to nociceptive skin stimulation in humans. A review of the literature
J. Neurophysiol. Clin.
(1999)
M. Frot et al.
Intracortical recordings of early pain-related CO2-laser evoked potentials in the human second somatosensory SII. area
Clin. Neurophysiol.
(1999)
M. Frot et al.
Responses of the supra-sylvian SII. cortex in humans to painful and innocuous stimuli. A study using intra-cerebral recordings
Pain
(2001)
R. Kakigi et al.
Pain-related magnetic fields following painful CO2 laser stimulation in man
Neurosci. Lett.
(1995)
P.E. Kinahan et al.
A direct comparison between whole-brain PET and BOLD fMRI measurements of single-subject activation response
NeuroImage
(1999)
V. Kunde et al.
Topography of middle-latency somatosensory evoked potentials following painful laser stimuli and non-painful electrical stimuli
Electroencephalogr. Clin. Neurophysiol.
(1993)

F. Mauguière et al.

Activation of a distributed somatosensory cortical network in the human brain. A dipole modelling study of magnetic fields evoked by median nerve stimulation. Part I: Location and activation timing of SEF sources

Electroencephalogr. Clin. Neurophysiol.

(1997)

I. Merlet et al.

Simplified projection of EEG dipole sources onto human brain anatomy

Neurophysiol. Clin.

(1999)

D. Miron et al.

Effects of attention on the intensity and unpleasantness of thermal pain

Pain

(1989)

E. Opsommer et al.

Dipole analysis of ultralate (C-fibres) evoked potentials after laser stimulation of tiny cutaneous surface areas in humans

Neurosci. Lett.

(2001)

R. Peyron et al.

Functional imaging of brain responses to pain. A review and meta- analysis 2000

Neurophysiol. Clin.

(2000)

R.D. Treede et al.

Cortical representation of pain: Functional characterization of nociceptive areas near the lateral sulcus

Pain

(2000)

M. Valeriani et al.

Scalp tompography and dipole source modelling of potentials evoked by CO2 laser stimulation of the hand

Electroencephalogr. Clin. Neurophysiol.

(1996)

M. Valeriani et al.

Sources of cortical responses to painful CO2: Laser skin stimulation of the hand and foot in the human brain

Clin. Neurophysiol.

(2000)

Q. Wu et al.

Hyperalgesia with reduced laser evoked potentials in neuropathic pain

Pain

(1999)

B. Bromm et al.

Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation

Hum. Neurobiol.

(1984)

B. Bromm et al.

Laser-evoked cerebral potentials in the assessment of cutaneous pain sensitivity in normal subjects and patients

Rev. Neurol.

(1991)

C. Buchel et al.

Dissociable neural responses related to pain intensity, stimulus intensity, and stimulus awareness within the anterior cingulate cortex: A parametric single-trial laser functional magnetic resonance imaging study

J. Neurosci.

(2002)

H. Burton et al.

Tactile-vibration-activated foci in insular and parietal-opercular cortex studied with positron emission tomography: Mapping the second somatosensory area in humans

Somatosens. Mot. Res.

(1993)

M.C. Bushnell et al.

Pain perception: Is there a role for primary somatosensory cortex?

Proc. Natl. Acad. Sci. USA

(1999)

P.B. Cipolloni et al.

Cortical connections of the frontoparietal opercular areas in the rhesus monkey

J. Comp. Neurol.

(1999)

R.C. Coghill et al.

Pain intensity processing within the human brain: A bilateral, distributed mechanism

J. Neurophysiol

(1999)

A.D. Craig et al.

Functional imaging of an illusion of pain

Nature

(1996)

A.D. Craig et al.

Thermosensory activation of insular cortex

Nat. Neurosci.

(2000)

K.D. Davis et al.

fMRI of human somatosensory and cingulate cortex during painful electrical nerve stimulation

NeuroReport

(1995)

K.D. Davis et al.

Functional MRI of pain- and attention-related activations in the human cingulate cortex

J. Neurophysiol.

(1997)

K.D. Davis et al.

Event-related fMRI of pain: Entering a new era in imaging pain

NeuroReport

(1998)

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The directional organization of multiple nociceptive regions, particularly within obscure operculoinsular areas, underlying multidimensional pain processing remains elusive. This study aims to establish the fundamental organization between somatosensory and insular cortices in routing nociceptive information. By employing an integrated multimodal approach of high-field fMRI, intracranial electrophysiology, and transsynaptic viral tracing in rats, we observed a hierarchically organized connection of S1/S2 → posterior insula → anterior insula in routing nociceptive information. The directional nociceptive pathway determined by early fMRI responses was consistent with that examined by early evoked LFP, intrinsic effective connectivity, and anatomical projection, suggesting fMRI could provide a valuable facility to discern directional neural circuits in animals and humans non-invasively. Moreover, our knowledge of the nociceptive hierarchical organization of somatosensory and insular cortices and the interface role of the posterior insula may have implications for the development of targeted pain therapies.
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How pain emerges from human brain remains an unresolved question in pain neuroscience. Neuroimaging studies have suggested that all brain areas activated by painful stimuli were also activated by tactile stimuli, and vice versa. Nonetheless, pain-preferential spatial patterns of voxel-level activation in the brain have been observed when distinguishing painful and tactile brain activations using multivariate pattern analysis (MVPA). According to two hypotheses, the neural activity pattern preferentially encoding pain could exist at a global, coarse-grained, regional level, corresponding to the “pain connectome” hypothesis proposing that pain-preferential information may be encoded by the synchronized activity across multiple distant brain regions, and/or exist at a local, fine-grained, voxel level, corresponding to the “intermingled specialized/preferential neurons” hypothesis proposing that neurons responding specially or preferentially to pain could be present and intermingled with non-pain neurons within a voxel. Here, we systematically investigated the spatial scales of pain-distinguishing information in the human brain measured by fMRI using machine learning techniques, and found that pain-distinguishing information could be detected at both coarse-grained spatial scales across widely distributed brain regions and fine-grained spatial scales within many local areas. Importantly, the spatial distribution of pain-distinguishing information in the brain varies across individuals and such inter-individual variations may be related to a person's trait about pain perception, particularly the pain vigilance and awareness. These results provide new insights into the longstanding question of how pain is represented in the human brain and help the identification of characteristic neuroimaging measurements of pain.
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Citation Excerpt :
The evoked pain cluster is related to symptoms concentrated around NPSI items assessing evoked pain phenomena such as pain after mechanical touch and due to cold stimulation. There is a wide literature on the role of the insula after thermal stimulation in healthy volunteers [34], and it has been shown that in patients with syringomyelia, discrete patterns of cortical fMRI are found after pain evoked by normally non painful stimuli, including the posterior insula and the adjacent parietal operculum and parts of S2 [18]. One of the theories supporting the effect of PSI-rTMS on nociception thresholds [16,30] and in clinical pain [24] is based on putative overriding effects (of 10 Hz stimulation for rTMS) on PSI local activity and disruption of its pro-nociceptive tonus.
The posterior-superior insula (PSI) has been shown to be a safe and potentially effective target for neuromodulation in peripheral neuropathic pain (PNP) in humans and animal models. However, it remains unknown whether there is a measurable responder profile to PSI stimulation. Two factors were hypothesized to influence the response of repetitive transcranial magnetic stimulation (rTMS) of the PSI: differences in rTMS target (discrete subregions of the PSI) or PNP phenotype.
This is a secondary analysis from a randomized, double-blind, sham-controlled, cross-over trial assessing PSI-rTMS in PNP (N = 31, 5 days rTMS) (10.1016/j.neucli.2021.06.003). Active PSI-rTMS true responders (>50% pain reduction from baseline after active but not after sham series of treatment) were compared with not true responders, to determine whether they differed with respect to 1) rTMS neuro-navigational target coordinates, and/or 2) specific neuropathic pain symptom inventory (NPSI) clusters (pinpointed pain, evoked pain, and deep pain) at baseline.
Mean rTMS target coordinates did not differ between true (n = 45.1%) and not true responders (p = 0.436 for X, p = 0.120 for Y, and p = 0.116 for Z). The Euclidian distance between true and not true responders was 4.04 mm. When comparing differences in responders between NPSI clusters, no participant within the evoked pain cluster was a true responder (p = 0.024).
Response to PSI-rTMS may depend on pain cluster subtype rather than on differences in targeting within the PSI.
Early nociceptive evoked potentials (NEPs) recorded from the scalp
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Citation Excerpt :
Additional scalp recording sites would have been necessary to provide a definite evidence about the distribution of N40, but our study was not aimed at obtaining a detailed map of the early waves, which will be investigated in future research. On the other hand, the very different latency ranges of the components and techniques of stimulus presentation do not allow comparisons with previous works on scalp distribution and depth recordings (Frot et al., 2014; Hu et al., 2014; Peyron et al., 2002; Valeriani et al., 2004), as they were focused on slower nociceptive afferents and late cortical events. Stimulation of the radial area with the unselective 1000 IDE evoked a cortical response (SEP) similar to the one obtained after stimulation of the nerve trunks, starting with the N20 component, albeit of smaller amplitude, confirming previous reports (Leandri et al., 2018).
Neurophysiological investigation of nociceptive pathway has so far been limited to late cortical responses. We sought to detect early components of the cortical evoked potentials possibly reflecting primary sensory activity.
The 150 IDE micropatterned electrode was used to selectively activate Aδ intraepidermic fibres of the right hand dorsum in 25 healthy subjects and 3 patients suffering from trigeminal neuralgia. Neurographic recordings were performed to assess type of stimulated fibres and check selectivity. Cortical evoked potentials were recorded from C3′-Fz and Cz-Au1.
Neurographic recordings confirmed selective activation of Aδ fibres. Early components were detected after repetitive stimulation (0.83/s rate and 250–500 averages); the first negative component occured at 40 ms (N40) on the contralateral scalp.
The provided data support the hypothesis that N40 could be the cortical primary response conducted by fast Aδ fibres.
This is the first report of early, possibly primary, cortical responses in humans by nociceptive peripheral stimulation. Although not perfected yet to allow widespread diagnostic use, this is probably the only method to allow fully objective evaluation of the nociceptive system, with important future implications in experimental and clinical neurophysiology.
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¹: To whom correspondence and reprint requests should be addressed at Department of Neurologie and Centre de la Douleur, Bellevue Hospital, CHU St-Etienne, Bd Pasteur, 42055 St-Etienne Cédex 02, France. Fax: (33) 04 77 12 05 43. E-mail: [email protected].

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Regular ArticleRole of Operculoinsular Cortices in Human Pain Processing: Converging Evidence from PET, fMRI, Dipole Modeling, and Intracerebral Recordings of Evoked Potentials

Abstract

Brain Res. Rev.

Electroencephalogr. Clin. Neurophysiol.

NeuroImage

Pain

J. Neurophysiol. Clin.

Clin. Neurophysiol.

Pain

Neurosci. Lett.

NeuroImage

Electroencephalogr. Clin. Neurophysiol.

Electroencephalogr. Clin. Neurophysiol.

Neurophysiol. Clin.

Pain

Neurosci. Lett.

Neurophysiol. Clin.

Pain

Electroencephalogr. Clin. Neurophysiol.

Clin. Neurophysiol.

Pain

Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation

Hum. Neurobiol.

Laser-evoked cerebral potentials in the assessment of cutaneous pain sensitivity in normal subjects and patients

Rev. Neurol.

Dissociable neural responses related to pain intensity, stimulus intensity, and stimulus awareness within the anterior cingulate cortex: A parametric single-trial laser functional magnetic resonance imaging study

J. Neurosci.

Tactile-vibration-activated foci in insular and parietal-opercular cortex studied with positron emission tomography: Mapping the second somatosensory area in humans

Somatosens. Mot. Res.

Pain perception: Is there a role for primary somatosensory cortex?

Proc. Natl. Acad. Sci. USA

Cortical connections of the frontoparietal opercular areas in the rhesus monkey

J. Comp. Neurol.

Pain intensity processing within the human brain: A bilateral, distributed mechanism

J. Neurophysiol

Functional imaging of an illusion of pain

Nature

Thermosensory activation of insular cortex

Nat. Neurosci.

fMRI of human somatosensory and cingulate cortex during painful electrical nerve stimulation

NeuroReport

Functional MRI of pain- and attention-related activations in the human cingulate cortex

J. Neurophysiol.

Event-related fMRI of pain: Entering a new era in imaging pain

NeuroReport

Regular Article
Role of Operculoinsular Cortices in Human Pain Processing: Converging Evidence from PET, fMRI, Dipole Modeling, and Intracerebral Recordings of Evoked Potentials