A novel approach to predict subjective pain perception from single-trial laser-evoked potentials
Introduction
Pain is an unpleasant multidimensional experience associated with real or potential tissue damage (Loeser and Treede, 2008). Therefore, pain experience does not simply reflect sensory information but can be substantially influenced by various psycho-social contexts (e.g., the gender of experimenter) (Aslaksen et al., 2007) and psycho-physiological factors (e.g., fluctuations in vigilance and attention). Since pain is a subjective first-person experience, self-report (e.g., Visual Analog Scales [VAS] and Numeric Rating Scales) is the gold standard for the determination of the presence, absence, and intensity of pain perception in clinical practice (Cruccu et al., 2010, Haanpaa et al., 2010). While self-report of pain provides important clinical information for the adequate treatment of pain patients in most situations (Brown et al., 2011), it fails to be used in some vulnerable populations (e.g., patients with disorders of consciousness, including coma, vegetative state, and minimally conscious state) (Schnakers and Zasler, 2007). Lack or any inaccuracy of pain assessment can lead to inadequate or suboptimal treatment of pain in these vulnerable patients, which may lead to various additional clinical problems (e.g., psychological distress or depression, the development of chronic pain) (Roulin and Ramelet, 2012, Zwakhalen et al., 2006). Although reliable pain assessment is important to adequately treat patients suffering from persistent pain (Gagliese and Melzack, 1997, Zwakhalen et al., 2006), it is extremely difficult to detect and monitor pain in specific clinical populations, such as non-communicative patients with disorders of consciousness (Schnakers et al., 2010). In addition, the brain damage of these patients may lead to confused, stereotyped, and uncoordinated behaviors (Roulin and Ramelet, 2012, Schnakers and Zasler, 2007), which is the barrier to adopt behavioral responses as pain indicators. Therefore, the availability of a physiology-based and objective assessment of pain that complements the self-report of pain would be of great importance in basic and clinical applications.
Nowadays, electroencephalographic (EEG) responses elicited by nociceptive laser heat pulses that selectively excite nociceptive free nerve endings in the epidermis (Bromm and Treede, 1984) are widely adopted to investigate the peripheral and central processing of nociceptive sensory input (Iannetti et al., 2003, Treede et al., 2003). Such laser-evoked potentials (LEPs) are mediated by the activation of type-II Aδ mechano-heat nociceptors (Treede et al., 1995) and spinothalamic neurons in the anterolateral quadrant of the spinal cord (Treede et al., 2003). LEPs consist of several transient responses that are time locked and phase locked to the onset of laser stimuli. The largest LEP response consists of a biphasic negative–positive complex (N2 and P2 waves), maximal at the scalp vertex (Bromm and Treede, 1984) and largely reflecting the activity of the bilateral operculoinsular and anterior cingulate cortex (Garcia-Larrea et al., 2003). The strong relationship between the N2 and P2 amplitudes in LEPs and the intensity of pain perception have been well characterized (Bromm and Treede, 1991, Garcia-Larrea et al., 1997, Iannetti et al., 2005, Kakigi et al., 1989), and the correlations between N2 and P2 latencies and the intensity of pain perception were also reported (Iannetti et al., 2005). All these findings inspire us to explore the possibility of objective assessment of pain based on the single-trial LEP features related to latencies and amplitudes of N2 and P2 waves.
The aim of the present study was to develop a novel approach to rapidly and reliably predict pain from single-trial LEP features (Fig. 1), which can be achieved through the following two major steps. First, a novel method that combines common spatial pattern (CSP) and multiple linear regression (MLR) was proposed to achieve an automated and reliable single-trial estimate of LEP features. Second, a Naïve Bayes classifier and a multiple linear prediction model were trained to respectively distinguish low and high pain and predict the intensity level of pain perception from single-trial LEP features. Such training and predicting were achieved at both within-individual level, where the classifier and prediction model were trained on and applied to single-trial LEPs from the same individual, and cross-individual level, where the classifier and prediction model were trained on a cohort of individuals and applied to another individual.
Section snippets
Experimental design and EEG recording
Twenty-nine healthy participants (9 females and 20 males) aged 17–25 years (mean 22.2 ± 1.9), without a history of chronic pain, participated in the study. All participants gave written informed consent, and the local ethics committee approved the experimental procedures.
Radiant-heat stimuli were generated by an infrared neodymium yttrium aluminum perovskite (Nd:YAP) laser with a wavelength of 1.34 μm (Electronical Engineering, Italy). Laser pulses activate directly nociceptive terminals in the
Laser-evoked brain responses
Laser stimuli elicited a clear pinprick perception and reproducible time-locked LEPs in all participants (mean VAS = 5.8 ± 1.2), related to the activation of Aδ fibers (Bromm and Treede, 1984). Fig. 2 shows the group-level average LEP waveforms at Cz (nose reference) and the scalp topographies of N2 and P2 waves for each level of pain perception intensity (I1–I4). Across subjects, latencies and amplitudes of N2 and P2 peaks for each level of pain perception intensity were as follows: N2 latency
Discussion
In the present study, we aimed at developing a fast, automated, and reliable approach for (1) estimating single-trial LEP features and (2) predicting pain perception from estimated single-trial LEP features. We applied a novel single-trial analysis approach that combined CSP and MLR to automatically and reliably estimate single-trial LEP features, and adopted a Naïve Bayes classifier to discretely predict low and high pain and a multiple linear prediction model to continuously predict the
Acknowledgments
LH and PX were supported by the National Natural Science Foundation of China (31200856), Natural Science Foundation Project of CQ CSTC, Special Financial Grant from the China Postdoctoral Science Foundation (2012T50755), and New Teacher Fund of Ministry of Education of China (20120182120002). GH, YSH and ZGZ were partially supported by a Grant (HKU 762111M) from the Hong Kong SAR Research Grants Council and a Grant (201211159074) from HKU CRCG. The collaboration between LH and GDI is generously
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These authors contributed equally.