Parallel spinal pathways generate the middle-latency N1 and the late P2 components of the laser evoked potentials
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
References (62)
- et al.
Anatomical localization and intra-subject reproducibility of laser evoked potential source in cingulate cortex, using a realistic head model
Clin Neurophysiol
(2002) - et al.
Single trial fMRI reveals significant contralateral bias in response to laser pain within thalamus and somatosensory cortices
Neuroimage
(2003) - et al.
Brain electrical source analysis of laser evoked potentials in response to painful trigeminal nerve stimulation
Electroenceph Clin Neurophysiol
(1995) - et al.
Neurophysiological evaluation of pain
Electroencephalogr Clin Neurophysiol
(1998) - et al.
Nociceptive responses of trigeminal neurons in SII-7b cortex of awake monkeys
Brain Res
(1989) - et al.
Intracortical recordings of early pain-related CO2-laser evoked potentials in the human second somatosensory (SII) area
Clin Neurophysiol
(1999) - et al.
Brain generators of laser-evoked potentials: from dipoles to functional significance
Clin Neurophysiol
(2003) - et al.
Intracortical recordings of pain related laser evoked potentials in the human cingulate cortex
Clin Neurophysiol
(2006) - et al.
Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser-evoked potentials in humans
Neuroscience
(2005) - et al.
Pain-related magnetic fields following painful CO2 laser stimulation in man
Neurosci Lett
(1995)
Estimation of conduction velocity of the human spinothalamic tract in man
Electroenceph Clin Neurophysiol
Primary somatosensory cortex is actively involved in pain processing in human
Brain Res
Topography of middle-latency somatosensory evoked potentials following painful laser stimuli and non-painful electrical stimuli
Electroenceph Clin Neurophysiol
Attentional modulation of the nociceptive processing into the human brain: selective spatial attention, probability of stimulus occurrence, and target detection effects on laser evoked potentials
Pain
Contribution of attentional and cognitive factors to laser evoked brain potentials
Neurophysiol Clin
Functional imaging of brain responses to pain. A review and meta-analysis
Neurophysiol Clin
A simple method for estimatine conduction velocità of the spinothalamic tract in healthy humans
Clin Neurophysiol
Left-hemisphere dominance in early nociceptive processing in the human parasylvian cortex
Neuroimage
What to learn from in vivo opioidergic brain imaging
Eur J Pain
Spinothalamocortical projections to the secondary somatosensory cortex (SII) in squirrel monkey
Brain Res
The cortical representation of pain
Pain
Clinical usefulness of laser-evoked potentials
Neurophysiol Clin
Laser-evoked potentials: normative values
Clin Neurophysiol
Multiple pathways for noxious information in the human spinal cord
Pain
Scalp topography and dipolar source modelling of potentials evoked by CO2 laser stimulation of the hand
Electroenceph Clin Neurophysiol
Sources of cortical responses to painful CO2 laser skin stimulation of the hand and foot in the human brain
Clin Neurophysiol
Segmental inhibition of cutaneous heat sensation and of laser-evoked potentials by experimental muscle pain
Neuroscience
Diencephalic mechanisms of pain sensation
Brain Res
Somatotopic organization along the central sulcus, for pain localization in humans, revealed by positron emission tomography
Exp Brain Res
Nerve fibres discharges cerebral potentials and sensations induced by CO2 laser stimulation
Human Neurobiol
From nociception to pain perception: imaging the spinal and supraspinal pathways
J Anat
Cited by (28)
Laser evoked potential amplitude and laser-pain rating reduction during high-frequency non-noxious somatosensory stimulation
2018, Clinical NeurophysiologyCitation Excerpt :1) It is possible that spinal pathway generating the N1 LEP component is minimally or not affected by non-painful electrical stimuli. Our previous study suggested that the vertex LEP component (N2/P2) and the lateralized N1 potential are generated by parallel spino-thalamic pathways with different conduction velocities (Valeriani et al., 2007). Thus, it is possible that the Aβ fibres inhibit the spinal fibres mediating the N2/P2 component, but not those generating the N1 response. (
Evaluation of afferent pain pathways in adrenomyeloneuropathic patients
2018, Clinical NeurophysiologyAssessing pain in patients with chronic disorders of consciousness: Are we heading in the right direction?
2017, Consciousness and CognitionDynamic construction of the neural networks underpinning empathy for pain
2016, Neuroscience and Biobehavioral ReviewsCitation Excerpt :The physical state of the observer is another important factor regulating the propensity to behave altruistically. The personal experience of pain makes individuals less prone to empathize with others, favoring the adoption of an egocentric stance, as demonstrated using laser evoked potentials (LEPs) (Valeriani et al., 2008), a neurophysiological tool to non-invasively explore the nociceptive system (Valeriani et al., 2007). This finding is consistent with studies showing that social stress decreases empathy in both mouse and human strangers (Martin et al., 2015) and that prior exposure to pain decreases activity in regions regularly associated with empathy for pain (Preis et al., 2015, 2013).
Peripheral sensitization reduces laser-evoked potential habituation
2015, Neurophysiologie CliniqueCitation Excerpt :An increase in latency and reduction in amplitude of the N1 component without affecting the N2/P2 component imply that central processing of painful laser stimuli has been altered, while peripheral signal transduction seems to be intact. Valeriani et al. showed that dissociated abnormalities of either N1 or N2/P2 LEP components can be found since N1 and N2/P2 components are generated by parallel pathways [33]. Speculatively, the LEP component N1 might indicate a shift of the sensitization effects from the anterior cingulate cortex (which is represented by the N2–P2 complex [20] to the operculoinsular cortex (which is represented by the N1 component [12,18], which develops over time and cannot be detected shortly after removing the capsaicin patch.