The primary somatosensory cortex largely contributes to the early part of the cortical response elicited by nociceptive stimuli

Abstract

Research on the cortical sources of nociceptive laser-evoked brain potentials (LEPs) began almost two decades ago (Tarkka and Treede, 1993). Whereas there is a large consensus on the sources of the late part of the LEP waveform (N2 and P2 waves), the relative contribution of the primary somatosensory cortex (S1) to the early part of the LEP waveform (N1 wave) is still debated.

To address this issue we recorded LEPs elicited by the stimulation of four limbs in a large population (n = 35). Early LEP generators were estimated both at single-subject and group level, using three different approaches: distributed source analysis, dipolar source modeling, and probabilistic independent component analysis (ICA).

We show that the scalp distribution of the earliest LEP response to hand stimulation was maximal over the central-parietal electrodes contralateral to the stimulated side, while that of the earliest LEP response to foot stimulation was maximal over the central-parietal midline electrodes. Crucially, all three approaches indicated hand and foot S1 areas as generators of the earliest LEP response.

Altogether, these findings indicate that the earliest part of the scalp response elicited by a selective nociceptive stimulus is largely explained by activity in the contralateral S1, with negligible contribution from the secondary somatosensory cortex (S2).

Introduction

Brief laser heat pulses selectively excite Aδ- and C-fiber epidermal free nerve endings (Bromm and Treede, 1984). Such stimuli elicit a number of transient brain responses (laser-evoked potentials, LEPs) in the ongoing electroencephalogram (EEG) (Carmon et al., 1976, Mouraux et al., 2003). These responses are mediated by the activation of type-II Aδ mechano-heat nociceptors (II-AMH) (Treede, 1995) and spinothalamic neurons in the anterolateral quadrant of the spinal cord (Treede, 2003). LEPs consist of a number of deflections. The largest of these deflections form a negative–positive complex (N2–P2), peaking at approximately 200–350 ms when stimulating the hand dorsum and maximal at the scalp vertex (Bromm and Treede, 1984). This complex is preceded by a smaller negative deflection (N1) peaking at approximately 160 ms when stimulating the hand dorsum and maximal over the central-temporal region contralateral to the stimulated side (Tarkka and Treede, 1993). Although Aδ-related LEPs are widely used to investigate the peripheral and central processing of nociceptive sensory input (Iannetti et al., 2003, Treede et al., 2003), and are currently considered the best available diagnostic tool to assess the function of Aδ nociceptive pathways in patients (Haanpaa et al., 2011), a full understanding of their functional significance remains to be achieved.

A crucial step in this direction is a compelling description of the cortical sources underlying the earliest part of the LEP response. Indeed, while there is converging evidence from dipolar modeling of both scalp and subdural recordings, as well as from direct intracranial recordings, that the bilateral operculoinsular cortex and the cingulate cortex generate, albeit with different contributions, the late-latency N2 and P2 waves (Frot and Mauguiere, 2003, Frot et al., 2007, Frot et al., 2008, Kakigi et al., 1995, Kanda et al., 2000, Perchet et al., 2008, Tarkka and Treede, 1993, Valeriani et al., 1996, Valeriani et al., 2000, Vogel et al., 2003), the contribution of the controlateral primary somatosensory cortex (S1) to the early latency N1 wave is much debated. In their seminal study, Tarkka and Treede (1993) indicated that the N1 wave was generated by concomitantly active sources in both the contralateral S1 and the bilateral S2. However, most of the subsequent source analysis studies proposed dipolar modeling solutions that either did not include an S1 source or did not observe an improvement of the fitting when an S1 source was included in the model (Bentley et al., 2001, Bromm and Chen, 1995, Nakamura et al., 2002, Schlereth et al., 2003, Valeriani et al., 1996, Valeriani et al., 2000, Valeriani et al., 2004). This has led some authors to conclude that the parasylvian region, rather than S1, was the earliest cortical structure to respond to nociceptive input in humans (Treede et al., 2000), while others considered that the absence of S1 activation could be only apparent, and due to a combination of technical and physiological factors (e.g., Kakigi et al., 1995). Thus, it is still unclear if and how much S1 contributes to the early part of the cortical response elicited by nociceptive stimuli. This issue is an important one, as the N1 wave of the LEPs has been recently demonstrated to represent somatosensory specific activities maximally reflecting the incoming nociceptive input (Lee et al., 2009, Mouraux and Iannetti, 2009) and to present theoretical advantages for clinical application, such as its lower sensitivity to attention and vigilance as compared to the later vertex complex (Cruccu et al., 2008, Garcia-Larrea et al., 1997).

In the present study we aimed to solve this issue conclusively, by recording 64-channel LEPs elicited by the stimulation of the four limbs, in a large population of healthy volunteers (n = 35). In order to compensate for the limited spatial resolution of the techniques used to infer the location of the neural sources underlying scalp ERPs, we analyzed the LEP data both at group and single-subject level, using three different source analysis approaches: distributed source analysis, dipolar source modeling, and probabilistic independent component analysis (PICA).