Original article
Brain generators of laser-evoked potentials: from dipoles to functional significanceGénérateurs corticaux des potentiels évoqués par laser : des dipoles à la signification fonctionnelle

https://doi.org/10.1016/j.neucli.2003.10.008Get rights and content

Abstract

In this work we review data on cortical generators of laser-evoked potentials (LEPs) in humans, as inferred from dipolar modelling of scalp EEG/MEG results, as well as from intracranial data recorded with subdural grids or intracortical electrodes. The cortical regions most consistently tagged as sources of scalp LERs are the suprasylvian region (parietal operculum, SII) and the anterior cingulate cortex (ACC). Variability in opercular sources across studies appear mainly in the anterior–posterior direction, where sources tend to follow the axis of the Sylvian fissure. As compared with parasylvian activation described in functional pain imaging studies, LEP opercular sources tended to cluster at more superior sites and not to involve the insula. The existence of suprasylvian opercular LEPs has been confirmed by both epicortical (subdural) and intracortical recordings. In dipole-modelling studies, these sources appear to become active less than 150 ms post-stimulus, and remain in action for longer than opercular responses recorded intracortically, thus suggesting that modelled opercular dipoles reflect a “lumped” activation of several sources in the suprasylvian region, including both the operculum and the insula. Participation of SI sources to explain LEP scalp distribution remains controversial, but evidence is emerging that both SI and opercular sources may be concomitantly activated by laser pulses, with very similar time courses. Should these data be confirmed, it would suggest that a parallel processing in SI and SII has remained functional in humans for noxious inputs, whereas hierarchical processing from SI toward SII has emerged for other somatosensory sub-modalities. The ACC has been described as a source of LEPs by virtually all EEG studies so far, with activation times roughly corresponding to scalp P2. Activation is generally confined to area 24 in the caudal ACC, and has been confirmed by subdural and intracortical recordings. The inability of most MEG studies to disclose such ACC activity may be due to the radial orientation of ACC currents relative to scalp. ACC dipole sources have been consistently located between the VAC and VPC lines of Talairach's space, near to the cingulate subsections activated by motor tasks involving control of the hand. Together with the fact that scalp activities at this latency are very sensitive to arousal and attention, this supports the hypothesis that laser-evoked ACC activity may underlie orienting reactions tightly coupled with limb withdrawal (or control of withdrawal). With much less consistency than the above-mentioned areas, posterior parietal, medial temporal and anterior insular regions have been occasionally tagged as possible contributors to LEPs. Dipoles ascribed to medial temporal lobe may be in some cases re-interpreted as being located at or near the insular cortex. This would make sense as the insular region has been shown to respond to thermal pain stimuli in both functional imaging and intracranial EEG studies.

Résumé

Ce travail est une revue des données de la littérature concernant les générateurs corticaux des réponses évoquées par une stimulation au laser (PELs) chez l'Homme. Cette revue regroupe les données des études de modélisation dipolaire des sources intra-cérébrales après enregistrement de surface en EEG et MEG, ainsi que les données obtenues grâce à des enregistrements intracérébraux, soit par grille sous-durale soit par enregistrement direct des structures corticales par électrodes implantées. Les régions corticales les plus communément considérées comme étant des sources des PELs sont la région supra-sylvienne (opercule pariétal, SII) et le gyrus cingulaire antérieur (GCA). On observe une certaine variabilité entre les différentes études dans la localisation des sources operculaires, et ce principalement le long d'un axe antéro-postérieur, où les sources tendent à suivre l'axe de la scissure de Sylvius. En comparant ces localisations avec celles des activations parasylviennes enregistrées en imagerie fonctionnelle, les sources des PELs operculaires sont situées plus haut (Z = 12–28 vs Z = –4–20) et n'incluent pas l'insula. La présence de PELs situées dans l'opercule a été confirmée aussi bien par des enregistrements sous-duraux que par des enregistrements par électrodes implantées directement dans le cortex. Dans les études de modélisation, ces sources semblent s'activer avant 150 millisecondes post-stimulus et rester actives plus longtemps que les réponses operculaires enregistrées directement en intra-cérébral. Ceci suggère que l'activité des dipôles modélisés dans l'opercule correspond en fait à un ensemble d'activités de plusieurs sources situées dans la région supra-sylvienne. La participation d'un dipôle situé dans l'aire SI pour expliquer la distribution de surface des PELs reste très controversée, mais il semble aujourd'hui de plus en plus probable que SI et l'opercule seraient activées de façon concomitante en réponse à une stimulation laser. Si ces données étaient confirmées, cela suggèrerait qu'un système de traitement de l'information en parallèle entre SI et SII aurait été conservé chez l'Homme pour la douleur, alors qu'un système plus hiérarchique de traitement de SI vers SII émergerait pour d'autres sous-modalités somesthésiques. Toutes les études de modélisation avec enregistrement EEG rapportent à ce jour l'existence d'une source située dans le GCA, activée avec une latence correspondant à celle du potentiel de scalp P2. Cette activation, également enregistrée en sous-durale ou à l'aide d'électrodes intra-cérébrales, est confinée à l'aire 24, dans la partie caudale du GCA. Les dipôles du GCA étant orientés radialement par rapport à la surface du scalp, cette activité cingulaire est difficilement mise en évidence par les études MEG. Dans la quasi totalité des études, les sources cingulaires sont situées entre les axes VCA et VCP de l'atlas de Talairach, proche de la partie du GCA impliquée dans le traitement de tâches mettant en jeu le contrôle moteur de la main. Ceci, associé au fait que les activités de surface enregistrées à cette latence sont très sensibles à l'attention–distraction, supporte l'hypothèse que les PELs cingulaires pourraient être liées à une réaction d'orientation à la stimulation couplée à un réflexe de retrait. Des sources des PELs ont quelquefois été localisées dans les régions pariétales postérieures, temporales médiales ou insulaires antérieures, mais beaucoup moins fréquemment que dans les aires citées précédemment. Les dipôles situés en premier lieu dans la zone temporale médiane ont parfois été ré-interprétés comme étant plutôt localisés au niveau du cortex insulaire, ce qui semble cohérent étant donné que, selon les études d'imagerie et d'enregistrements intra-cérébraux, l'insula participerait activement au traitement des informations thermiques à caractère douloureux.

Introduction

Since their introduction by Carmon and his colleagues in the mid-1970s [16], [69], laser-evoked brain potentials (LEPs), and more recently laser-evoked magnetic fields (LEFs), have progressively found their place in both the clinical evaluation of patients with pain, and the investigation of cortical mechanisms sub serving the conscious, normal or abnormal pain sensation. The first decade of LEP utilisation was mainly devoted to demonstrating the selective action of laser stimuli on nociceptive skin afferents (see Plaghki et al., this volume), as well as the potential use of scalp responses in assessing damage to nociceptive pathways (see Treede et al., this volume). These aspects of LEP research were conducted using a very limited number of recording electrodes (often less than five), as they did not require a precise knowledge of the brain generators of scalp responses. The anatomical regions contributing to the responses recorded from the scalp have been progressively disclosed during the past 10 years, mainly using multi-channel recordings (20–128 electrodes or magnetic sensors), followed by source localisation methods (dipolar modelling) that use mathematical models of both the bio-electrical generators and the volume conductor where they lie. Dipolar modelling estimates the site and the orientation of intracerebral sources by comparing the scalp distribution of electromagnetic fields predicted by a given intracranial generator (modelled as a current dipole) and the actual distribution of these fields over the scalp. The solution is iteratively optimised until the predicted and the observed spatio-temporal fields are (ideally) coincident (for comprehensive and critical reviews see [43], [91], [94]). The advent of magnetoencephalographic (MEG) techniques capable to resolve overlapping sources near the scalp surface (which are often lumped in EEG recordings), has contributed precious data to the disclosure of early generators from SI and SII. On the other hand, EEG recordings have proved so far more powerful than MEG to demonstrate deep sources radial to the scalp surface, such as those arising from the anterior cingulate gyrus. One possible drawback of modelling studies is that investigators may be drawn towards trying similar solutions as previously described, thus creating a vicious circle where previous errors may have perpetuated. We try in this work to review critically this issue when relevant to the results, and to contrast as much as possible the reports on dipole modelling with those from comparable animal studies, when available, functional imaging and especially intracranial recordings in humans. In recent years, laser-evoked responses recorded with intracranial electrodes, either subdural or intracortical, have greatly contributed to refine our interpretation of modelling studies, favouring certain solutions to the detriment of others.

In this paper, we review and analyse critically previous EEG and MEG results on the anatomical sources of LEPs, including recent data from our laboratories, and provide some tentative hypotheses on the functional significance of generators so far disclosed.

Section snippets

Pioneering studies: suprasylvian opercular sources, including second somatic area (SII)

The three seminal modelling studies on LEP generators [9], [96], [102] were obtained using the same modelling algorithm based on spatio-temporal modelling with fixed (i.e. non-moving) dipoles (BESA; [94]). In spite of different stimulation sites (hand or temple), variable number of electrodes in each case (15 vs. 20 vs. 31), and different laser types (CO2 vs. thulium-YAG 1

Primary sensory cortex (SI)

In their pioneer dipole EEG study, Tarkka and Treede [96] suggested that a SI source was active simultaneously to, or even later than, suprasylvian areas. However, while the involvement of opercular areas proved to be a most consistent finding in subsequent work (see above), the presumed activation of SI was not reproduced in other modelling studies, either using EEG with up to 64 recording electrodes [4], [9], [19], [102], [104], or MEG with up to 74 channels [52], [72], [111], [114].

Anterior cingulate cortex

In EEG modelling studies, sources in the anterior cingulate cortex (ACC) have been almost as frequently described as those in suprasylvian regions, and this either after conventional A-delta stimuli [9], [88], [96], [102], [103] or following specific C-fibre excitation [22], [47], [73]. The latency times of ACC activation, although slightly variable across studies, lie within the window of the main biphasic vertex LEP (N2-P2) component. Although the anterior–posterior axis of the ACC is very

Other sources (insular, mesio-temporal and frontal lobe generators)

Some other sources have been occasionally described in EEG modelling and MEG studies but with much less consistency than the above-mentioned areas. In the study of Bentley et al. [4], the N1-N2 LEP responses (150–250 ms) to A-delta stimuli were not explained by opercular sources, but rather by a posterior parietal generator, followed by cingulate (400 ms) and anterior insular (800 ms) responses, without opercular contribution. The presence of insular-generated responses to A-delta inputs had

Conclusion

The cortical regions most consistently tagged as sources of scalp LERs are the suprasylvian region (parietal operculum, SII) and the anterior cingulate cortex (ACC); their activity in response to laser has been supported by intracranial recordings. Primary somatosensory sources are also probably active in response to laser, their response being largely parallel to that of opercular sources. Insular responses are also supported by intracranial recordings but have been described less consistently

Acknowledgements

This work was supported in part by a Grant of the CNP Foundation against pain (Fondation CNP, “Etude électrophysiologique et clinimétrique des facteurs de survenue de la douleur neuropathique”) to Luis Garcia-Larrea, and by a Grant of the UPSA Institute for pain to Maud Frot (“Enregistrements intracorticaux des réponses aux stimulations nociceptives”).

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