Parallel spinal pathways generate the middle-latency N1 and the late P2 components of the laser evoked potentials

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Abstract

Objective

To investigate the possible presence of multiple spino-thalamic pathways with different conduction velocities (CVs) in the human spinal cord.

Methods

Laser evoked potentials (LEPs) were recorded in 10 healthy subjects after stimulation of the dorsal midline at four vertebral level: C5, T2, T6, and T10. This method allowed us to minimize the influence of the conduction in the peripheral fibers and to calculate the spinal CV in two different ways: (1) the reciprocal of the slope of the regression line was obtained from the latencies of the different LEP components, and (2) the distance between C5 and T10 was divided by the latency difference of the responses at the two sites. In particular, we considered the middle-latency N1 potential (latencies of around 135, 150, 157, and 171 ms after stimulation at C5, T2, T6, and T10 levels, respectively), which is generated in the second somatosensory (SII) area, and the late P2 response (latencies of around 336, 344, 346, and 362 ms after stimulation at C5, T2, T6, and T10 levels, respectively), which is generated in the anterior cingulate cortex (ACC).

Results

The calculated CV of the spinal fibers generating the N1 potential (around 9 m/s) was significantly different (P < 0.05) from the one of the pathway producing the P2 response (around 13 m/s).

Conclusions

Our results suggest that the N1 and the P2 LEP components are generated by two parallel spinal pathways.

Significance

Both the N1 and P2 potentials should be recorded in the clinical routine since a dissociated abnormality of either response may be found in lesions of the nociceptive system not only in the brain, but also at spinal cord level.

Introduction

Pain is a multidimensional experience including sensory-discriminative and affective-emotional components (Melzack and Casey, 1968). In man, the different pain aspects have been separated at cortical level by neuroimaging techniques. While the sensory-discriminative component of pain has been associated with brain activity in the primary (SI) and secondary (SII) somatosensory areas (Anderrson et al., 1997, Peyron et al., 2000, Bingel et al., 2003, Vogel et al., 2003), the affective and emotional properties of the pain experience are processed in the anterior cingulate cortex (ACC) (Rainville et al., 1997, Peyron et al., 2000, Petrovic et al., 2002, Sprenger et al., 2005). Studies in animals suggested that the anatomical structures corresponding to the different pain components are possibly segregated as from the spinal cord. Traditionally, the sensory-discriminative component of pain is thought to be served by a lateral pain system starting from wide dynamic range (WDR) neurons responding to noxious stimuli in lamina V; their fibers arrive at the ventro–postero inferior (VPI) and ventro–postero lateral (VPL) nuclei of the thalamus, which project to the SI and SII areas (Melzack and Casey, 1968, Kenshalo et al., 1980, Spreafico et al., 1987, Stevens et al., 1993, Price, 2000, Craig, 1995). The emotional-affective aspect of pain, instead, is believed to correspond to the medial pain system whose spinal cells in lamina I project to the medial thalamic nuclei and, from there, to the ACC (Craig et al., 1989, Stevens et al., 1989). According to an alternative view, mainly derived from studies in primates, inputs from nociceptive neurons (NS) of lamina I ascend through the spino-thalamic tract (STT) and reach two main thalamic relays, namely the posterior part of the ventral medial nucleus (VMpo) and the ventral caudal portion of the medial dorsal nucleus (MDvc) (Craig et al., 1994). While inputs from VMpo reach the somatosensory and insular cortices, the MDvc neurons project to the anterior cingulate gyrus (Craig, 2003). It is noteworthy that all these anatomical data agree in showing parallel nociceptive pathways which serve the somatosensory cortices and the cingulate cortex, respectively.

The most reliable neurophysiological tool to assess the human nociceptive system function is represented by the laser evoked potential (LEP) recording. The study of the scalp LEPs offers a unique opportunity to explore non-invasively the nociceptive pathways, from the transduction of the painful stimulus into neural signals up to the transmission of the nociceptive inputs and their cerebral processing. Indeed, microneurographic studies demonstrated that CO2 laser pulses delivered on the hairy skin activate specifically the thin nociceptive Aδ and C fibers, without any concurrent stimulation of the non-nociceptive Aβ afferents (Bromm and Treede, 1984). In particular, LEPs obtained after painful stimulation of the skin show a latency range of 100–450 ms, depending on the stimulation site as well as on the physical properties of the laser source, the skin pigmentation and thickness, and are generated by Aδ-fiber inputs (Bromm and Lorenz, 1998). Scalp LEPs include two main components, the earlier of which, labelled as N1, is recorded in the temporal region contralateral to the stimulated side, while the second, represented by a biphasic negative-positive complex (N2–P2), is obtained on the Cz vertex. LEP intracerebral recording studies demonstrated that the N1 potential is generated in the SII area (Frot et al., 1999), while the N2–P2 complex is originated from the ACC (Lenz et al., 1998). In particular, the P2 potential may be considered as the main marker of the genuine ACC activity, while other neural sources, such as those in the bilateral SII area (Valeriani et al., 1996, Valeriani et al., 2000, Garcia-Larrea et al., 2003), in the insula (Valeriani et al., 1996, Garcia-Larrea et al., 1997, Frot and Mauguière, 2003) and, maybe, in the SI area (Kanda et al., 2000, Ohara et al., 2004) contribute with the ACC to the N2 response generation. As compared to the P2 potential, the N1 response is less reduced in amplitude by distraction from the laser stimulus, thus it has been linked to the sensory-discriminative component of pain (Garcia-Larrea et al., 1997, Garcia-Larrea et al., 2003). On the contrary, the vertex LEP components, in particular the P2 potential, are extremely sensitive to cognitive factors, e.g., distraction from the painful stimulus (Garcia-Larrea et al., 1997), and are thought to represent the neurophysiological counterpart of the affective-emotional aspect of pain experience (Lorenz and Garcia-Larrea, 2003).

The velocity of the human STT conduction has been measured by using LEPs. In particular, an elegant and easy method was developed by Cruccu’s group (Cruccu et al., 2000, Iannetti et al., 2003) who delivered laser pulses on the skin overlying the vertebral spinous processes at different levels so to reduce the peripheral conduction to the minimum [see Iannetti et al. (2001) for a clear description of the advantage of this method over others]. STT conduction velocity (CV) was calculated as the reciprocal of the slope of the regression line for the LEP latencies obtained at all sites of stimulation along the spine. The resulted CV of the STT fibers generating the P2 potential was 11.9 m/s (Iannetti et al., 2003), thus confirming previous results obtained by a different method (Kakigi and Shibasaki, 1991, Rossi et al., 2000).

The aim of our study was to measure the CV of the STT fibers generating both the N1 and P2 potentials in the same subjects by stimulating the skin of the dorsal midline at different vertebral levels. On the base of the anatomical studies in animals (see above), we hypothesized that the N1 and P2 LEP components are generated by different spino-thalamic pathways, thus also the corresponding CVs might be different.

Section snippets

Subjects

Ten healthy right-handed subjects (5 males, 5 females, mean age 32.4 ± 6.6 years), who gave their informed consent, took part in our study. The study conformed to the standards set by the Declaration of Helsinki.

CO2 laser stimulation and LEP recording

During LEP recording, the subjects lay prone on a couch in a warm and semi-dark room. Cutaneous heat stimuli were delivered by a CO2 laser (10.6 μm wavelength, 2 mm beam diameter, 10 ms pulse duration – ELEN, Florence, Italy) on skin overlying the C5, T2, T6, and T10 vertebral spinous

Subjective measures

No difference was found in pain ratings at different spine levels (F = 1.91; p = 0.15).

CO2 laser evoked potentials

In all our subjects, it was possible to recognize the negative N1 response in both the temporal electrodes (T3 and T4). At about the same latency, the positive P1 potential was recorded by the Fz lead. Previous literature demonstrated that the N1 and P1 potentials represent the negative and positive poles, respectively, of a dipolar source having a tangential orientation in the perisylvian region and a

Discussion

The main result of the present study is that there are two segregated spinal pathways, with different CVs, which convey the neural inputs due to cutaneous heat stimuli and generate the middle-latency N1 and the late P2 potential, respectively.

Conclusion

Our results not only confirm that the STT fibers generating the P2 potential have a CV of around 13 m/s (Kakigi and Shibasaki, 1991, Rossi et al., 2000, Iannetti et al., 2003), but they are the first to show that the spinal afferents generating the N1 response are segregated from those of the P2 LEP component. Tsuji et al. (2006) failed in showing any statistically significant difference between the CV of the spinal fibers reaching the SII and the CV of the pathway for the ACC.

A clinical

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