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REPORT

Laser-Evoked Potentials Are Graded and Somatotopically Organized Anteroposteriorly in the Operculoinsular Cortex of Anesthetized Monkeys

¹Institute of Physiology and Pathophysiology, Johannes Gutenberg University, Mainz, Germany; and ²Atkinson Research Laboratory, Barrow Neurological Institute, Phoenix, Arizona

Submitted 12 May 2006; accepted in final form 5 August 2006

	ABSTRACT

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The operculoinsular cortical region has a major role in the representation of noxious stimuli, based on functional imaging observations, clinical lesion studies, and EEG recordings of specifically pain-related laser-evoked potentials (LEPs) in humans. The source of LEPs has not been identified, and several somatic representations and cytoarchitectonic areas may be present in this complex region. To overcome the limitations of human studies, a primate model is needed in which the main LEP generator in this region can be localized and characterized using invasive methods. We obtained EEG recordings of evoked responses to noxious laser stimulation at different intensities and performed dipole source analyses in three anesthetized macaque monkeys. We show that LEPs can be recorded that 1) grade with stimulus intensity, 2) display two distinct responses corresponding to the "late" (A-fiber) and the "ultralate" (C-fiber) LEPs recorded in humans, and 3) originate deep within the operculoinsular region, thus establishing a valid primate model for experimental analysis of LEPs. Further, we found that LEPs elicited from the leg, arm, and ear display a global somatotopy organized in the posteroanterior direction (leg posterior and arm and ear anterior), which contrasts starkly with the mediolateral (leg to face) gradient of the somatotopic representations in primary and secondary somatosensory cortices. These results provide evidence that the main generator of pain-related activity in operculoinsular cortex may participate in both the somatic localization and the intensity discrimination of pain sensations, and they indicate that it may be distinct from the traditional somatosensory cortices.

	INTRODUCTION

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The operculoinsular cortex has been identified as an important nociceptive region in humans by several methods, including EEG recordings of laser-evoked potentials (LEPs) and functional imaging (Apkarian et al. 2005). To investigate the cortical representation of pain, the most specific stimulus available is a noxious heat pulse generated by brief infrared laser stimulation. Laser pulses activate nociceptive A- and C-fibers in humans and monkeys, without concomitant activation of tactile afferents, and generate prominent LEPs within the brain that can be recorded from the surface of the cortex or from the scalp in awake humans (Bromm et al. 1984; Treede et al. 1995). The earliest cortical LEP correlates with pain sensation in several ways, and dipole source reconstruction analyses indicate that its main source lies in the contralateral operculoinsular region (Garcia-Larrea et al. 2003; Iannetti et al. 2005; Vogel et al. 2003). This observation is consistent with clinical findings that lesions of operculoinsular cortex in humans can disrupt both the somatic localization and the discrimination of intensity and quality of pain sensations (Greenspan et al. 1999; Schmahmann and Liefer 1992).

The identity of the main LEP generator in operculoinsular cortex has not been established. Recent evidence suggests that the operculoinsular region may contain multiple somatosensory areas with different somatotopic representations of the body, different cytoarchitectonic structure, and probably different functions (Craig 2002; Disbrow et al. 2000; Eickhoff et al. 2006). Most authors ascribe the main LEP source to the secondary somatosensory cortex (S2) in the parietal operculum. In that view, based on the concept that the pain system is separated into a lateral part subserving sensory-discriminative functions and a medial part processing the affective-motivational pain component (Melzack and Casey 1968), painful sensations are first discriminated and localized by activation of somatosensory cortices S1 and S2, and a pathway through medial thalamus produces affect-related activity in the anterior cingulate cortex (Apkarian et al. 2005; Garcia-Larrea et al. 2003). In that view, the earliest cortical LEP in the operculoinsular region should be somatotopically organized in the mediolateral (foot to face) direction, consistent with the organization of S2. An alternate view is that the operculoinsular LEP is generated by a direct lamina I spino–thalamo–cortical pathway to the dorsal posterior insula (dpIns; Craig 2002, 2003; Vogel et al. 2003). In this view, there are two fundamentally different sets of primary somatic afferent representations in cortex: one set associated with sensorimotor integration (control of skeletal muscle) and tactition that is somatotopically organized in the medial to lateral direction (i.e., S1 and S2); and another set associated with homeostasis (control of smooth muscle) and feelings from the body related to its physiological condition, including pain, temperature, itch, and sensual touch, that is somatotopically organized in the orthogonal posterior to anterior direction (i.e., dpIns). In this view, the earliest cortical LEP in the operculoinsular region should be somatotopically organized in the posteroanterior (foot to face) direction (Craig 2004). Studies of LEPs in humans have not determined a somatotopic organization that could distinguish between these two basic possibilities. Although particular studies localized the main LEP generator to the region ofdpIns baseon dipole source reconstruction algorithms (e.g., Kakigi et al. 2003; Opsommer et al. 2001; Vogel et al. 2003), without microelectrode mapping using depth recordings such localization is inherently uncertain.

Strong activation in the operculoinsular region during painful stimulation has also been revealed by functional imaging studies in awake humans (Apkarian et al. 2005; Peyron et al. 2002). However, the few functional magnetic resonance imaging (fMRI) studies that examined the somatotopic organization of pain-related responses in this region produced varying results, in large part because of the methodological limitations in spatial resolution (Bingel et al. 2004; Brooks et al. 2005; Ferretti et al. 2004; Valeriani et al. 2000). Thus identification and characterization of the pain-related LEP source(s) within operculoinsular cortex require detailed evidence at a higher resolution than practicable in humans, and an experimental primate model is needed that can be used for invasive studies. Before performing invasive single- or multiunit recordings in the monkey, it is necessary first to localize the region(s) within the operculoinsular cortex that are active during pain processing. Dipole source analysis based on EEG recordings of nociceptive-specific LEPs can provide such localization if applied in a valid primate model of human LEP recordings. Nevertheless, awake monkeys do not tolerate laser-evoked pain stimulation above threshold (Beydoun et al. 1997) and, because LEPs have not been reported previously in humans or monkeys under anesthesia, it has been presumed that anesthesia prevents such recordings (Garcia-Larrea et al. 2003). Thus in the present experiments, we sought first to determine whether LEPs can be recorded in the anesthetized monkey, then to determine whether such recordings provide a valid model of human LEPs, and finally to explore whether a somatotopic organization might be discernable that could test whether the main generator can be ascribed to S2 or to dpIns.

	METHODS

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We deeply anesthetized (stage 4) three cynomolgus monkeys (Macaca fascicularis, 3–4 kg, either sex) with alphaxalone/alphadalone (Saffan, 12–18 mg · kg^–1 · h^–1; Glaxo) by continuous infusion through an angiocath in the saphenous vein placed under ketamine sedation (25 mg, administered intramuscularly). Heart rate, blood pressure, end-tidal CO₂, and core temperature were monitored, and the level of anesthesia was verified by areflexia, heart rate, and EEG activity (burst suppression). This anesthetic agent was chosen because, although it depresses forebrain activity similarly to barbiturates and volatile agents, it preserves homeostatic afferent activation (Lumb and Lovick 1993). We applied eye salve and a topical anesthetic (Cetacaine; Cetylite, Pennsauken, NJ) in the ear canals before mounting each animal in a stereotaxic headholder. These procedures conform with National Institutes of Health policies and they were approved by the animal welfare committee of the Barrow Neurological Institute.

Laser stimuli (Sharplan CO₂ laser, 10.6 µm, defocused beam diameter 5 mm) were applied sequentially (n = 5–20, interstimulus interval about 4 s) to adjacent spots within small regions of the monkeys' shaved hairy skin on the left foot, leg, hand, finger, arm, and outer ear. In a few runs, symmetrical skin sites on the right side were stimulated also. Laser-evoked potentials (LEPs) were recorded from nine EEG leads (eight active pin electrodes for unipolar EEG derivations and one common reference electrode); the pins were inserted transcutaneously in the scalp in the configuration shown in Fig. 1A (impedance <5 kOhms, band-pass 0.2–100 Hz, vs. Fz reference). Graded stimulation was delivered at intensities below and above that which produce pricking pain in humans (1–6 W x 100 ms; 5–30 mJ/mm²). Different stimulus intensities were applied either in ascending or randomized order. Averaged evoked potentials were recorded using a Nicolet Viking IV-P and printed records were produced.

View larger version (59K): [in this window] [in a new window]   FIG. 1. A: locations of the EEG recording sites are shown on a photograph of the superior surface of one monkey's head (left) and in the polar coordinate system of the computer modeling reconstruction (right). Four temporal recording sites are not visible in the photograph. B: original oscillographic laser-evoked potential (LEP) averages from all 8 active electrodes evoked from 2 stimulus sites in a single case (AT50). Short-latency (A-fiber) LEP replaces the long-latency (C-fiber) LEPs at higher stimulus intensities, and it is graded with stimulus intensity. Small dots indicate stimulus delivery times, which are also demarcated by a pulse artifact in the records. Traces 1–8 are from electrodes 1–8 referenced to Fz (electrode 9). Negativity is plotted upward.

	RESULTS

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Characterization of short- and long-latency responses after laser stimulation

Depending on stimulus intensity, we found two different types of responses after laser stimulation.

1. ) Stimulation at pricking pain (high) intensities (>2 W) evoked LEPs with a bilateral temporal negativity and an anterior midline positivity at latencies of 160–200 ms (Fig. 1B). Latencies in each animal were shorter for more proximal stimulus sites and for greater stimulus intensities. Notably, the magnitude of these short-latency LEPs graded with increasing stimulus intensity, as is evident in the original records shown in Fig. 1B. Figure 2A shows the graded relationship between stimulus intensity and the magnitude of the signals recorded bilaterally at the temporal leads. Analyses using ANOVA showed a significant main effect of stimulus intensity [F_(3,152) = 32.6, P < 0.001].
   
2. ) Stimulation at lower intensities (1–2 W), which produce either no sensation or sensations of warming or burning pain in humans, either elicited no response or evoked LEPs at distinctly longer latencies of about 600 ms. Stimulation at intermediate stimulus intensities (2–4 W) generally produced either a long-latency LEP (at about 600 ms) or a short-latency LEP (at about 160–200 ms). With increased stimulus intensity, the latency of the long-latency LEP did not gradually diminish to that of the short-latency LEP; rather, the long-latency LEP generally appeared only in the absence of the short-latency LEP. Figure 2B shows quantitatively how the appearance of the long-latency LEP was "occluded" by the appearance of the short-latency LEP.
   

View larger version (11K): [in this window] [in a new window]   FIG. 2. A: graded short-latency LEP amplitudes (baseline to peak) at left (T5) and right (T6) temporal leads as a function of stimulus intensity (means ± SE). B: incidence of the short-latency and long-latency LEPs varied inversely with stimulus intensity, so that the long-latency (C-fiber) LEP generally appeared only in records in which the short-latency (A-fiber) LEP was absent (total number of data sets = 82).

Somatotopic organization of LEPs

The recordings in all three cases showed a posterior to anterior somatotopic organization that was evident first in the spline maps of the surface topographies and second in the reconstructions of the dipole source locations. Figure 3A shows the surface topographies of the short-latency LEP peaks recorded over the contralateral scalp in response to stimulation of the foot, hand, and ear in case 541206. Because there is no monkey head model available for this visualization, the spline maps are shown on the surface of a human dummy head. The strong negative focus visibly shifts progressively farther anterior for each somatotopic location, with virtually no apparent shift in the mediolateral direction. Similar results were obtained in all three animals.

View larger version (43K): [in this window] [in a new window]   FIG. 3. A: isopotential maps (superimposed on a model human head) showing the surface topographies at the peak of the short-latency LEPs evoked from the foot, hand, and ear. Strong negative focus (N1) visibly shifts progressively farther anterior for each somatotopic location. B: horizontal (axial) projection plot summarizing the locations of the operculoinsular dipole sources of the short-latency LEP peaks for all 3 somatic stimulation sites in all 3 monkeys. Foot/leg source was posterior to the hand/arm and ear sources in all cases, and the hand/arm was posterior to the ear in 2 of the 3 cases. Numbers indicate distances in the reconstruction model of the human brain, which is about 2.1-fold larger than the actual monkey brains in this study. Anterior (up) and posterior (down) boundaries of the brain were located at y = +65 and –65 mm, respectively. Different symbols represent different monkeys and stimulus locations (blue = AT50, red = AT7X, green = 541206; triangle = ear, circle = hand/arm, square = foot/leg). Bars indicate SE of repeated estimates. C: 3-dimensional rendering based on an anatomical MRI acquired for one monkey that shows the overall somatotopic oganization of the estimated cortical locations of the operculoinsular LEP sources for the 3 stimulation sites from one case (AT50).

Figure 3C shows the estimated dipole locations from one case (AT50) superimposed directly on a cutaway anatomical MRI view of the monkey's head and brain. The figure clearly illustrates, first, the localization of the LEP dipole sources to the operculoinsular region and, second, the overall anteroposterior somatotopy of the LEP sources within this region.

	DISCUSSION

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These observations provide two significant results. First, they document for the first time the presence of graded LEPs in the anesthetized macaque monkey. A previous study reported short-latency (A-fiber) LEPs recorded in awake monkeys; however, the monkeys accepted laser stimulation only at nociceptive threshold at the base of the tail (Beydoun et al. 1997), and graded stimulation could not be used. Long-latency (C-fiber) LEPs were not previously recorded in monkeys. LEPs were not previously recorded under anesthesia in either humans or monkeys (Garcia-Larrea et al. 2003). Second, the present observations provide strong and consistent evidence, from both surface topographies and dipole source reconstructions, that the primary LEP generator in the operculoinsular region of primate cortex is organized somatotopically with an anteroposterior (face to foot) gradient.

LEPs in anesthetized monkeys have characteristics that correspond very well with the earliest LEPs described in awake humans. The earliest identifiable signals consisted of a bilateral negativity in temporal leads (N1) concurrent with a midline frontal positivity. Dipole source analysis in humans showed that this scalp topography is mainly attributed to bilateral sources in the operculoinsular region (Garcia-Larrea et al. 2003). Similarly, our dipole reconstructions show that LEPs in the monkey seem to originate from cortical source(s) deep within the operculoinsular region. We did not observe the later vertex potentials (N2–P2 LEPs) that have been associated with arousal and perception in humans (Garcia-Larrea et al. 2003). We infer that the underlying bases for the LEPs we recorded are robustly activated primary cortical receptive areas, because under deep anesthesia the coordinated intracortical network interactions necessary for behavioral responsiveness in the awake primate are presumably not available. The midline LEP source observed occasionally in these data probably corresponds to the midcingulate source that has been identified in human LEP and imaging studies (Garcia-Larrea et al. 2003; Schlereth et al. 2003). Another LEP source in area 3a, or alternatively areas 1–2, of the S1 sensorimotor region was also reported by some studies in humans (Ohara et al. 2004; Ploner et al. 2000; Schlereth et al. 2003) and, although that source was not identified in the reconstructions from the present scalp recordings, it has been predicted by anatomical and physiological work in the monkey (Craig 2003; Kenshalo et al. 2000) and should be observable with focal depth recordings in the anesthetized monkey (as they have been in rat; Kalliomäki et al. 1993). We conclude that the present observations define a valid primate model that can be used for invasive functional anatomical experiments designed to identify the ascending pathway for human pain-related LEPs, to characterize their cortical sources, and to explore the interconnectivity of these primary sites.

The detailed characteristics of the LEPs we recorded provide further support for this conclusion. LEPs with an N1-like scalp topography appeared in two distinct latency ranges. The short-latency LEP was graded with stimulus intensity and it correlated with A-fiber activity. In contrast, the long-latency LEP appeared at lower stimulus intensities, it was "occluded" by the short-latency LEP, and it correlated with peripheral C-fiber activity. Thus these LEPs correspond directly with the so-called "late" and "ultralate" LEPs identified in humans (Cruccu et al. 2003; Granovsky et al. 2005; Magerl et al. 1999). Comparison of human LEPs and psychophysics with monkey primary afferent discharges suggested that these findings reflect different heat thresholds of A- and C-fiber nociceptors (Treede et al. 1994, 1995). Although the initial report of "late" and "ultralate" LEPs in humans reported only vertex potentials with A- and C-fiber latencies (Bromm et al. 1983), more recent studies found two responses that seem to originate from the same cortical source(s) in the operculoinsular cortex (Iannetti et al. 2005; Kakigi et al. 2003; Mouraux et al. 2004; Opsommer et al. 2001).

The second major result of the present observations is that the primary LEP generator in the operculoinsular region of primate cortex is organized somatotopically with an anteroposterior gradient. This result fits very well with functional anatomical evidence in the monkey indicating that nociceptive- and thermoreceptive-specific activity is conveyed to dpIns by a lamina I spino–thalamo–cortical pathway that is topographically organized in the anteroposterior direction (Craig 2003).

There is very little prior information on the organization of operculoinsular LEPs in humans that can be compared. Our findings are consistent with a report that LEPs from the face seemed to originate from a dipole source anterior to sources associated with LEPs from hand or foot in one patient (Vogel et al. 2003). Our findings are also consistent with a report that intracortical stimulation in the operculoinsular region elicited pain in the face from sites that seemed to be anterior to those where pain in the limbs was elicited (Ostrowsky et al. 2002). In contrast, one LEP study in humans sought but found no evidence of topography in operculoinsular cortex (Valeriani et al. 2000). We infer that, with surface EEG recordings, the somatotopic gradient of the main LEP source might be more apparent in the much smaller brain of the macaque monkey, in which the main generator in operculoinsular cortex is probably a proportionally much larger portion of the entire brain than in the human.

Previous functional imaging studies of pain-related activity in the operculoinsular region in humans also provide inconsistent evidence of somatotopy. One fMRI study of laser-evoked pain reported a mediolateral topography in the parietal operculum, but that conclusion may have been confounded by the inclusion of multiple sites within the region of interest in a group analysis (see Table 4 in Bingel et al. 2004). Another fMRI study of pain-related activation in operculoinsular cortex distinguished two sites but found no pain-related topography using electrical skin stimulation (which is not a selectively painful stimulus; Ferretti et al. 2004). Two recent fMRI studies of human thermal sensation reported an anteroposterior topography in the dpIns, one for activation by noxious heat and one for activation by innocuous cooling, consistent with our observations; nevertheless, the separation of the activation sites in both of these studies was at the limit of spatial resolution (Brooks et al. 2005; Hua et al. 2005).

The present demonstration that operculoinsular LEPs are both graded and somatotopically organized suggests that the underlying primary generator could participate in both the intensity discrimination and the somatic localization of pain sensations. It can be expected that any cortical region involved in these haptic sensory functions would show these characteristics, yet further evidence is needed to support this inference. Clinical lesion evidence is partly consistent. Thus lesions involving the operculoinsular region (including dpIns) were observed in patients that had selective contralateral hypoalgesia to contact heat and pinprick (Greenspan et al. 1999; see also Biemond 1956). Damage to the operculoinsular region was the common finding in eight patients with poststroke (pseudothalamic) central pain syndrome, in which the contralateral loss of acute pain and temperature sensation is diagnostic (Schmahmann and Liefer 1992). Contralateral loss of pain sensation was ascribed to a lesion of S1 in one patient by Ploner et al. (2000), although the patient had dense thermanesthesia and the illustrated lesion involved dpIns. On the other hand, Berthier et al. (1988) described six patients with "pain asymbolia" that had unilateral lesions involving the insula. They stated that these patients reported no unpleasantness and failed to show emotionally appropriate responses to painful heat and pinprick, yet had "normal pain thresholds" to electrical stimulation; however, these patients also failed to withdraw from visual or auditory threats and showed contralateral neglect, similar to the anosognosia recently described for patients with insular lesions (Karnath et al. 2005), which may reflect the role of the middle and anterior portions of the insula in emotional awareness (Craig 2002).

Notably, the posterior to anterior (foot to face) gradient we observed is orthogonal to the medial to lateral (foot to face) somatotopy of S2 and S1 (Disbrow et al. 2000). Therefore this finding contradicts the commonly espoused view that the primary LEP source in the operculoinsular region originates from S2. Rather, our observations indicate that the primary LEP generator in operculoinsular cortex is distinct from S2. Thus these observations support the emerging view that the primary cortical representation of pain-related activity in operculoinsular cortex is part of a set of representations of feelings from the body related to homeostasis (in dpIns; Craig 2002; Vogel et al. 2003), rather than part of the fundamentally distinct set of somatic afferent representations that are involved in sensorimotor integration and tactition (S1 and S2). Prior studies of pain-related activation in the operculoinsular region did not recognize this dual representation of somatic afferent activity. Although there may be secondary LEP sources in the operculoinsular region, only this view provides a cogent explanation for a recent clinical report (Mazzola et al. 2006) that operculoinsular stimulation sites that produced discretely localized pain sensations in human patients were clustered near the fundus of the circular sulcus (i.e., in the dpIns), rather than in the parietal operculum (i.e., S2).

In conclusion, the present observations define a primate model for analysis of pain-related LEPs, and they indicate that the primary LEP source in the operculoinsular cortex is distinct from S2 and yet seems capable of participating in both the intensity discrimination and somatic localization of painful stimuli. Future invasive studies using the present experimental LEP model will be able to identify precisely the sources of the operculoinsular and other LEPs in the primate brain and characterize them functionally and anatomically.

	GRANTS

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This work was supported by Deutsche Forschungsgemeinschaft Grant Tr 236/13–3, National Institute of Neurological Disorders and Stroke Grant NS-41287, and the Barrow Neurological Foundation.

	ACKNOWLEDGMENTS

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We thank M. Auldridge, J. Barber, and L. Brady for technical assistance.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence: A. D. Craig, Atkinson Research Laboratory, Barrow Neurological Institute, 350 West Thomas Rd., Phoenix, AZ 85013 (E-mail: bcraig{at}chw.edu)

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