Chapter 9 Event-related components of laser evoked potentials (LEPs) in pain stimulation: recognition of infrequency, location, and intensity of pain

Functional Neuroscience: Evoked Potentials and Related Techniques (Supplements to Clinical Neurophysiology, Vol. 59) Editors: C. Barber, S. Tsuji, S. Tobimatsu, T. Uozumi, N. Akamatsu, A. Eisen © 2006 Elsevier B.V. All rights reserved

61

Chapter 9

Event-related components of laser evoked potentials (LEPs) in pain stimulation: recognition of infrequency, location, and intensity of pain Masutaro Kanda* Department of Brain Pathophysiology, Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507 and Department of Neurology, Takeda General Hospital, Kyoto 601-1495 (Japan)

1. Introduction Painful stimulation with short-pulse CO2 laser was introduced by Mor and Carmon (1975) which, unlike electric shock, activates nociceptive receptors selectively and generates pure pain sensation (Bromm et al., 1984). Information about the activation is conducted through both small myelinated Aδ- and unmyelinated C-fibers and reaches the cerebral cortex via the spinothalamic tract (Bromm and Treede, 1987). Somatosensory evoked potentials (SEPs) following CO2 laser stimulation, known as laser evoked potentials (LEPs), are mainly composed of 3 components (N1, N2, and P2) (Miyazaki et al., 1994; Xu et al., 1995). The peak latencies of these components were reported as about 150 ms for N1, 220 ms for N2, and 330 ms for P2 (Miyazaki et al., 1994). LEPs are influenced by attention modulations and cognitive tasks. It was reported that N1, N2, and P2 of

*Correspondence to: Masutaro Kanda, M.D., Department of Neurology, Takeda General Hospital, 28-1 Moriminamimachi, Fushimi-ku, Kyoto 601-1495, Japan. Tel: +81-75-572-6331; Fax: +81-75-571-8877; E-mail: [email protected]

LEPs were modulated by attention, the components of which are arousal, vigilance, alertness or sustained attention, selective or focused attention, and executive attention (Beydoun et al., 1993; Miyazaki et al., 1994; García-Larrea et al., 1997; Legrain et al., 2002; Lorenz and García-Larrea, 2003). It was also reported that event-related potentials (ERPs) were evoked following P2 by using cognitive tasks when recording LEPs. In this chapter, I have focused on the previous studies in which ERPs of LEPs were evoked using an oddball task (Kanda et al., 1996), a point localization task (Kanda et al., 1999), and a pain intensity assessment (PIA) task (Kanda et al., 2002). 2. Oddball paradigm In an oddball paradigm, a distinct “target” stimulus is presented infrequently and at random intervals within a series of frequent “regular” stimuli (Sutton et al., 1965). Brain activities are recorded as P300 or P3 in response to target stimulus, which is the characteristic endogenous positive wave (Donchin et al., 1978, 1986). Towell and Boyd (1993) demonstrated a positive potential following P2 in response to the target CO2 laser stimulus in an oddball paradigm. However, the field

62 distribution of that potential, effects of different response tasks, and differences from other stimulus modalities remained unclear. Therefore, the aim of this study was to clarify the characteristics of the endogenous, cognitive component of LEPs by employing an oddball paradigm. In 12 healthy subjects, CO2 laser stimuli were frequently delivered to the ulnar side of the left-hand dorsum while rarely to the radial side of the same hand. The stimulated sides for frequent and rare were exchanged with each other from session to session. The subjects were instructed to either count mentally or press a button in response to the “target” rare stimuli delivered at a probability (p) of 0.2. Likewise, electric stimuli for the target were applied to either the second or fourth digit of the left hand at p = 0.2, while those for frequent were applied to the other of these two digits. For auditory stimulation, the 2000 Hz tone was presented binaurally at p = 0.2 as target stimulus, while the 1000 Hz tone was frequently presented. Electroencephalograms (EEGs) were recorded from electrodes placed on the scalp; Fpz, F3, Fz, F4, T3, C3, Cz, C4, T4, P3, Pz, P4, O1, Oz, and O2 according to the International 10–20 system. For each session, responses to frequent stimuli and target stimuli were separately averaged and time-locked to the stimulus onset. In the oddball paradigm using laser stimulation, N2 and P2 of LEPs were recorded maximally at Cz regardless of oddball conditions (frequent or rare) and response tasks (mental count or button press). Neither of the two components showed differences in the latency, amplitude, or scalp topography between the oddball conditions or between response tasks. Only in response to the target stimuli, another positive component (593 ± 31 ms, 10.6 ± 3.8 μV for the count and 560 ± 54 ms, 10.5 ± 1.8 μV for the button press responses) was recorded maximally at Pz following P2, called as “laser P3.” “Electric P3” was recorded in response to target electric stimuli (425 ± 69 ms, 11.2 ± 3.7 μV for the count and 417 ± 58 ms, 12.2 ± 5.5 μV for the button press responses) and “auditory P3” in response to the target auditory stimuli (351 ± 31 ms, 11.7 ± 4.8 μV for the count, and 336 ± 38 ms, 13.4 ± 5.9 μV for the button press responses), both of which were maximal at Pz. There was no statistical difference in amplitude or scalp topography among laser, electric, and auditory P3.

The longer latency of laser P3 compared with electric or auditory P3 can be mainly explained by its slower impulse conduction of Aδ-fiber through which peripheral activation by laser stimulus was conducted. Since laser P3 was recorded only after the target presentation regardless of the type of response task and showed the same scalp topography as that of electric or auditory P3, it is suggested that laser P3 is mainly related to the categorization process and shares the same mechanism of auditory or electric P3 reported to be generated in multiple brain areas (Nishitani et al., 1998). As neither N2 nor P2 differed in latency, amplitude or scalp topography between oddball conditions or response tasks, it is postulated that these two are mainly pain-related components of LEPs. 3. Localization of the pain spot A great advantage of using CO2 laser stimulus is that the stimulus spot can be chosen irrespective of the peripheral nerve pathways. It is therefore expected that when recording LEPs, the subject would, at least to some extent, perform a discriminative task to identify the location of the pain spot for each CO2 laser stimulus; if so, this corresponds to “point localization” that forms a cortically dependent sensory function (Corkin et al., 1970; Bassetti et al., 1993; Kim and Choi-Kwon, 1996). If this is the case, LEPs might contain ERPs that reflect the process of point localization of the pain spot. Therefore, the aim of this study was to demonstrate ERPs during the point localization of pain caused by CO2 laser stimulation. Painful CO2 laser stimuli were delivered to the dorsum of either hand in 16 healthy subjects. While the stimulus spot (pain spot) was shifted for each stimulus, the subject was requested to identify the stimulated spot as accurately as possible and to use a pointer in the non-stimulated hand to indicate the corresponding spot on a picture of a hand projected onto a screen (localization condition). For the control condition, the subject was instructed to point to a single predetermined spot, regardless of the location of the stimulated spot (control motor task condition). In the control rest condition, neither point localization nor the motor task was requested. EEGs were recorded from 21 electrodes

63 placed on the scalp: Fp1, Fpz, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, Oz, and O2 according to the International 10–20 system. They were referenced to the linked earlobes, and were averaged time-locked to the stimulus onset for each task separately. Under the control rest condition, N2 and P2 of LEPs were recorded. During the control motor task condition, a steep negative slope (NS′) was recorded at the frontocentral region following P2, indicating movementrelated cortical potentials (MRCPs) (Neshige et al., 1988). Exclusively during the localization condition, a positive peak (647 ± 89 ms, 5.6 ± 2.9 μV for the left and 634 ± 58 ms, 5.7 ± 2.7 μV for the right-hand stimulation) was identified and called the “localizationrelated potential (LP)”, which was maximal at the midline centro-parietal area and symmetrically distributed over the scalp. Neither the latency nor amplitude was significantly different between the stimulated hands. It is suggested that the LP is related to the somatotopic point localization of the pain spot. Its scalp distribution, showing midline centro-parietal distribution, suggests that it is most likely related to activation of the superior parietal cortices bilaterally, since it was reported that a superior-posterior stroke caused cortical sensory syndrome consisting of an isolated loss of discriminative sensation (stereognosis, graphesthesia, and joint position sense) involving one or two parts of the body (Bassetti et al., 1993). Another possibility is that LP as well as oddball P3 might be generated from multiple brain areas including those located in the bilateral temporal lobes and the second somatosensory cortex, because it was reported that auditory P3, which shows midline centro-parietal distribution, was generated by the contribution of multiple structures including the mesial temporal, superior temporal, and inferior parietal regions on both hemispheres (Nishitani et al., 1998). 4. Pain intensity assessment (PIA) The visual analogue scale (VAS) has been commonly used as a self-rating score of subjective pain intensity in clinical as well as experimental settings (Price et al., 1983). There have been no reports referring to a component of LEPs related to the measurement of pain

intensity, although by using strong electric shocks as painful stimuli, Becker et al. (2000) found late brain potentials relating to the measurement of pain intensity. In this study, therefore, LEPs were recorded using CO2 laser stimuli of various intensities, while the subject was required to measure on VAS the subjective intensity of pain evoked by the stimuli. In 12 healthy subjects, three kinds of CO2 laser stimuli were delivered to the left-hand dorsum at irregular intervals of 4–6 s, while the irradiation duration of each stimulus was randomly set to 40, 60, or 80 ms. For the VAS, a 50-cm long horizontal line was drawn on a screen placed 1.5 m in front of the subject. The line was labeled “no pain” at the left end and “the most intense pain imaginable” at the right. The subject was requested to assess the intensity of each pain stimulus and to move a pointer in their right hand to point to the VAS scale according to the subjective feeling of pain sensation (PIA condition). For the control condition, the subject was asked to move the pointer to the midpoint of the VAS line irrespective of the pain intensity (control motor task condition). In the control rest condition, neither PIA nor a motor response was required. EEGs were recorded from 21 electrodes placed on the scalp: Fp1, Fpz, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, Oz, and O2 according to the International 10–20 system. They were referenced to the linked earlobes, and were averaged time-locked to the stimulus onset for each type of stimulus as well as for each task condition. The VAS scores were 2.8 ± 0.5/10 for a stimulus of 40 ms duration, 4.8 ± 0.8/10 for 60 ms, and 6.1 ± 0.9/10 for 80 ms, and showed a highly significant positive correlation with the stimulus duration. Following the N2 and P2 of LEPs which were affected by stimulus duration but not modulated by task conditions, a positive peak was identified exclusively under the PIA condition regardless of the stimulus intensity and was called the “intensity assessment-related potential (IAP)”. The peak latencies of IAP were 642 ± 64 ms for a stimulus duration of 40 ms, 612 ± 92 ms for 60 ms, and 619 ± 76 ms for 80 ms, and their amplitudes were 8.2 ± 4.2, 7.1 ± 5.7, and 9.4 ± 5.6 μV, respectively. The IAP was maximal at the midline parietal area and symmetrically distributed over the scalp. Neither the

64 latency nor amplitude of the IAP was significantly different among three different stimulus intensities. Regarding N2 and P2, the latency of N2 was not significantly different among three conditions or among three stimulus durations, while that of P2 was significantly correlated with the stimulus duration. The amplitudes of both components were significantly correlated with the stimulus duration. It is the existence of an actual stimulus, regardless of its intensity, that operates the psychophysical processes involved in the VAS for the sensory intensity dimension of pain. As IAP did not differ in the latency, amplitude, or scalp distribution among the three different levels of stimulus intensity, it was indicated that the single major factor in the generation of IAP is the existence of pain stimulus but not its given or perceived intensity. These features of IAP fulfill most of the requirements for an endogenous component of ERPs (Donchin et al., 1978, 1986). From its scalp distribution, it can be assumed that the assessment of pain intensity involves multiple areas in both hemispheres. 5. Discussion Characteristic features of laser P3, LP, and IAP, and are shown in Table 1. For the tasks, laser P3 is related to the categorization process, LP is the precise localization,

and IAP is the intensity assessment of pain stimulus. The probability of the stimulus was one of the major factors for laser P3, but not for LP or IAP. These differences suggest that the three ERPs can be distinguished from each other. However, the possibility that LP and IAP are P3-like potentials cannot be rejected, because the waveform, latency, and scalp distribution were similar among the 3 ERPs (Table 1). Previous reports on LEPs using cognitive tasks are listed in chronological order (Table 2). Towell and Boyd (1993) reported laser P3 for the first time, and six authors have employed an oddball paradigm. Zaslansky et al. (1996) reported that P2 is involved in an oddball component, although other studies using an oddball paradigm showed that laser P3 corresponded to the oddball component (Towell and Boyd, 1993; Kanda et al., 1996; Legrain et al., 2002, 2003a, b). While we introduced the localization task that demonstrated the LP, two other authors used similar tasks. Valeriani et al. (2000) reported an early potential (eP) preceding N1 unmasked by a localization task, and Bentley et al. (2004) identified N1 enhancement with a localization task. Although we introduced a pain intensity assessment task that demonstrated the IAP, no other report using a similar task has been reported. In an oddball paradigm, Legrain et al. (2002) studied the LEPs of attended and unattended hands for

TABLE 1 TABLE 2 CHARACTERISTIC FEATURES OF LASER P3, LP, AND IAP Laser P3 Task Categorization Precise localization Intensity assessment Probability (%) Waveform Latency (ms) Amplitude (μV) Scalp distribution Maximum Symmetry Extension

LP

PREVIOUS REPORTS ON LEPs USING COGNITIVE TASKS

IAP Authors

Task Oddball paradigm Oddball paradigm Oddball paradigm Localization task Localization task Pain intensity assessment task Oddball paradigm for attended hand and unattended hand 3-stimulus oddball paradigm 3-stimulus oddball paradigm Localization task

Yes No No 20 Positive 580 10.6

No Yes No 100 Positive 630 5.7

No No Yes 100 Positive 625 8.2

Towell and Boyd (1993) Kanda et al. (1996) Zaslansky et al. (1996) Kanda et al. (1999) Valeriani et al. (2000) Kanda et al. (2002) Legrain et al. (2002)

Pz Yes Parietal

Cz or Pz Yes Parietal

Pz Yes Parietal

Legrain et al. (2003a) Legrain et al. (2003b) Bentley et al. (2004)

65 frequent and “target” rare stimuli, and compared each LEP component obtained in these 4 conditions. Their results were as follows: N1 and N2 were modulated by the direction of spatial attention, P2 was affected by the probability of the stimulus regardless of the spatial attention, and an additional parietal P600 was induced by attended rare stimuli, which could be seen as P3b. To study P3a or novelty P3, Legrain et al. (2003a, b) recorded LEPs in a three-stimulus oddball paradigm, in which frequent and “target” rare laser stimuli were given to one hand while “distractor” rare laser stimuli were given to the other hand. It was shown that targets and distractors elicited a late positive complex (LPC) around 465–500 ms and concluded that distractor LPC corresponds to P3a indexing an involuntary orientation of attention toward an unexpected new/deviant event. Taking these reports into account, it is suggested that

laser P3, LP, and IAP, which had peak latencies at about 600 ms, may share the same property with P3b but not P3a. In summary, components of LEPs and their modulation of attention and cognition are schematically shown in Fig. 1. Valeriani et al. (2000) reported an eP unmasked by using a localization task. N1 and N2 are influenced by various attention modulations (Beydoun et al., 1993; Miyazaki et al., 1994; García-Larrea et al., 1997; Legrain et al., 2002; Lorenz and García-Larrea, 2003). P2 is affected by the stimulus probability (Legrain et al., 2002). Distractor LPC corresponds to P3a (Legrain et al., 2003a, b). Laser P3, LP, and IAP are cognitive components generated in multiple brain areas, which share the same time range with P3b activities. This is also consistent with the notion that most neuronal processes specific to pain in the

Fig. 1. Schematic representation of LEP components. The solid line shows the LEP influenced by attention modulations and cognitive tasks while the interrupted line shows the LEP without these effects. A localization task unmasks a positive early potential (eP). Both N1 and N2 increased in amplitude by paying attention to the laser stimuli. The amplitude of P2 is larger after rare stimuli compared with that after frequent stimuli, independent of paying attention to the stimuli. Both target and distractor stimuli elicited a late positive complex (LPC) around 465–500 ms. Distractor LPC corresponds to P3a that indexes involuntary orientation of attention toward an unexpected new/deviant event. Laser P3 is recorded in the oddball paradigm, localizationrelated potential (LP) in the point localization task condition, and pain intensity assessment potential (IAP) in the task to assess pain intensity by means of the visual analogue scale (VAS), which appears at about 600 ms, corresponding to the time range with P3b activities.

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