Pain quality of thermal grill illusion is similar to that of central neuropathic pain rather than peripheral neuropathic pain

Introduction

The thermal grill illusion (TGI) can induce illusory pain in the absence of nociceptive input [1]. In the TGI paradigm, alternating innocuous cold and warm stimuli on the skin can induce a painful sensation [1]. Several neurophysiological studies have revealed supraspinal involvement in the TGI phenomenon [2], [3], [4], [5], [6]. A previous functional brain imaging study demonstrated that the TGI activates the nociceptive processing system in the central nervous system including the thalamus and the anterior cingulate cortex [3], [7]. In addition to supraspinal involvement, spinal nerves also contribute to the perception of the TGI [8], [9], [10]. These neural substrates are involved in nociceptive pain as well as pathologic neuropathic pain including spinal cord injury-related pain and post-stroke pain [11], [12], [13].

Patients with neuropathic pain complain of a complex quality of pain. For example, burning and electric shock-like pain have been classically assumed to be characteristic qualities of neuropathic pain, but throbbing indicates a nociceptive characteristic of pain [14]. Pain quality has been considered to indicate the underlying mechanism(s) of pain [15], and assessment of pain quality might make it possible to determine whether certain patterns of pain qualities moderate the effects of treatment [16]. Focusing on the pain quality described by subjects experiencing TGI-induced pain, the TGI paradigm was originally developed to create synthetic heat perception and TGI-induced pain is frequently described as “burning” [5]. Other terms including aching, throbbing, sharp, and itching were sporadically reported in small numbers of subjects [17], [18], [19]. In the present study, we analyzed and characterized the pain qualities of TGI-induced pain. Burning and other qualities described by subjects experiencing TGI-induced pain are similar to those observed in patients with neuropathic pain. To describe the pain qualities of the TGI and discriminate whether these qualities matched the pain qualities of central or peripheral neuropathy, we analyzed and compared pain qualities in central or peripheral neuropathic pain with reference to pain qualities of TGI-induced pain.

Experiment 1

In Experiment 1, we evaluated the qualities of TGI induced-pain in healthy participants using principal component analysis (PCA).

Methods

Participants

Overall, 148 participants (71 males and 77 females, aged 20–22 years), who were undergraduate students from Kio University, provided written informed consent and participated in this study. No participant had any neurological and/or psychiatric disorders. Eleven participants did not perceive any pain during the application of the thermal grill illusion, and therefore about 90% of the participants (n=137), who experienced TGI sensation, were included in the following analysis. The study protocol was in accordance with the Declaration of Helsinki and the protocol was approved by the ethics committee of the Kio University Health Science Graduate School (approval number: H30-11).

TGI apparatus

A custom-built TGI device was used, in which thermal stimuli were applied by eight copper bars (length 20 cm; diameter 0.8 cm; thickness 0.1 cm). Each copper bar was separated from its neighbor by 5 mm (Figure 1). Four of the bars were connected to a circulating thermostatic chamber (LBX-300, AS ONE Co.) with plastic tubes that kept the bars warm, and the other four were connected to an identical thermostatic chamber that kept the bars cool. The warm bars and the cool bars alternated to induce the TGI. Two thermometer probes (Unique Medical Co., Ltd) were attached to the bars (one cool bar, one warm bar) to monitor tube-surface temperatures during the experiment. As previously described [20], bar temperatures were set at 40 °C (warm) and 16 °C (cool), respectively. As previously demonstrated, the bar temperature alone did not induce a painful sensation [21], [22], [23]. However, the temperature difference between the bars [24], [25], [26] was reported to induce greater TGI-related pain in 70–90% of healthy participants compared with other conditions (e.g., 40 and 20 °C temperature bars) [27], [28].

Figure 1:

Experimental setup of the thermal grill illusion (TGI).

Procedure

Participants sat in front of the table on which the TGI apparatus rested. Participants were asked to put their left hand onto the grill (i.e., across the eight copper bars) for 60 s. None of the participants were informed about the temperature settings of the bars and the TGI phenomenon. Before obtaining informed consent, it was explained to participants that this experiment investigated somatosensory functions and that their hand would not be harmed even though they might feel painful sensations. Before starting the study procedure, the patients were instructed to concentrate and remember the perceptions of their hand during the study and to answer the questionnaires about these perceptions immediately after the procedure. After removing their hand from the grill, they rated the pain intensity of the experiment using the Short Form McGill Pain Questionnaire version-2 (SF-MPQ-2), which is an established questionnaire to assess the quality of pain [29]. The SF-MPQ-2 consists of 18 sensory items and four affective items [30]. In Experiment 1 with healthy participants, answering all the items in the full version of the MPQ (78 items) was considered difficult because the TGI experience is acute and it was likely that the participants might forget their perceptual experience when answering many questions. Therefore, we used only the sensory items of the SF-MPQ-2 (18 items) for an accurate evaluation of TGI-induced pain qualities. All sensory items in the SF-MPQ-2 are related to painful sensations as follows: throbbing pain, shooting pain, stabbing pain, sharp pain, cramping pain, gnawing pain, hot-burning pain, aching pain, heavy pain, tender, splitting pain, electric-shock pain, cold-freezing pain, piercing, pain caused by light touch, itching, tingling or pins and needles, and numbness. To avoid complications, we omitted the word “pain” to express pain qualities in the above sensory items. Participants were asked to rate their pain intensity in the TGI experiment to each item on a scale of 0 (none) to 10 (worst possible). Participants who rated at least one or more points on any of the sensory items of the SF-MPQ-2 were considered TGI-induced pain respondents and we analyzed all the TGI-induced pain respondents. Criteria of the TGI-induced pain respondents might have influenced the higher proportions than those in previous studies [27], [28].

Analysis

Because we aimed to explore the specific sensory aspects of TGI-induced pain, we used 18 sensory items of the SF-MPQ-2 (throbbing, shooting, stabbing, sharp, cramping, gnawing, hot-burning, aching, heavy, tender, splitting, electric-shock, cold-freezing, piercing, pain caused by light touch, itching, tingling or pins and needles, and numbness).

We calculated the median value for each item of the SF-MPQ-2 and generated a histogram. We extracted items for median values that were 1 or greater, and then used these items as TGI-induced pain qualities. Principal component analysis (PCA) was conducted with promax rotation to specify components of the TGI-induced pain quality using IBM SPSS Statistics, version 24 (IBM Corp., Armonk, NY, USA). This statistical procedure summarizes the data of pain qualities and makes it easier to determine the componential characteristics of pain qualities [15]. When conducting the PCA, items were removed if they did not have component loadings >0.5.

Results

The histogram and median value for each SF-MPQ-2 item are shown in Figure 2. Among the 18 sensory items of SF-MPQ-2, items with median values of 1 or greater were: throbbing, sharp, shooting, heavy, hot-burning, aching, electric-shock, cold-freezing, itching, and numbness. The PCA successfully divided these 10 items into two components. Finally, component 1 was characterized by high component loading on aching, throbbing, heavy and burning pain (Table 1) and Component 2 consisted of itching, electrical-shock, numbness, and cold-freezing (Table 1). Two residual items (sharp and shooting) failed to have a high component loading, and these were not characterized as TGI-induced pain qualities. The two-component structure was also confirmed by a scree plot of the eigenvalues (Component 1 = 4.31, Component 2 = 1.23). The calculated Kaiser-Meyer-Olkin (KMO) was 0.83 and Bartlett’s test p-value was less than 0.0001, indicating that the results of the PCA were valid for this data set [31]. Cronbach’s alpha values were 0.77 (Component 1) and 0.73 (Component 2). Because these values were located between 0.70 and 0.95, the results of the PCA are considered valid [32].

Figure 2:

Histogram for each item on the Short Form McGill Pain Questionnaire version-2 (SF-MPQ-2). Median: Median value on the SF-MPQ-2 (0; none, 10; worst possible).

Table 1:

Principal component analysis with loadings of the pain qualities reported for the thermal grill illusion (TGI).

	Component
	1	2
Aching	0.91	−0.28
Throbbing	0.76	0.13
Hot-burning	0.73	0.04
Heavy	0.63	−0.01
Sharp	0.46	0.34
Shooting	0.39	0.41
Itching	−0.37	0.87
Electric-shock	0.11	0.72
Numbness	0.12	0.70
Cold-freezing	0.13	0.58

Experiment 2

Using healthy participants, we identified two components of pain quality related to TGI-induced pain. Next, we investigated whether patients with neurological conditions complained of pain qualities similar to that of TGI-induced pain. In Experiment 2, we analyzed pain qualities in clinical patients with central neuropathic pain (spinal cord injury related pain, post-stroke pain) and peripheral neuropathic pain (trigeminal neuralgia, postherpetic neuralgia) using multiple correspondence analysis (MCA) and cross-tabulation.

Results

Figure 3 shows a geometrical representation of the MCA findings. This visually specified four pain qualities (hot-burning, aching, cold freezing and numbness) that were representative of central neuropathic pain (SCI-related pain and post-stroke pain), but not peripheral neuropathic pain (TN) and postherpetic neuralgia (PHN). These collective pain qualities explained 24.1% of data variability in Axis 1, where Cronbach’s α=0.61. Axis 2 explained data variability with an inertia value of 15.75%, where Cronbach’s α=0.33. Cross tabulation clarified that electrical-shock and heavy in addition to these four items were statistically characterized as pain qualities representing central neuropathic pain (p<0.05). Comparing the percentage of each pain quality for each type of neuropathic pain, we found that hot-burning, aching, heavy, cold-freezing, numbness and electrical-shock were more frequent in patients with central neuropathic pain (SCI-related pain and post-stroke pain) than peripheral neuropathic pain (TN, PHN).No statistically significant relationships were found between two residual pain qualities (throbbing and itching) and either type of neuropathic pain (p>0.05). Cross tabulation confirmed the relationship revealed by visually-manifested associations in the MCA (Figure 4). The result of the MPQ sensory items is shown in the Supplementary Table.

Figure 3:

Multiple correspondence analysis (MCA) demonstrating the associations between pain qualities (squares) and neurological disease (black circle). Red squares: component 1 of pain quality induced by TGI. Blue squares: component 2 of pain quality induced by TGI.

Figure 4:

Percentage of patients with each pain quality in each type of neuropathic pain.

*Significant relationship between pain quality and neurological disease with cross tabulation analysis (p<0.05). Red bars: component 1 of pain quality induced by TGI. Blue bars: component 2 of pain quality induced by TGI.

Discussion

TGI-induced pain is an experience of misperception actualizing synthetic pain without any nociceptive input in the periphery. Our participants most frequently described TGI-induced pain as hot-burning in accord with previous reports [17, 24, 38]. In addition to hot-burning pain, TGI-induced pain was also characterized as cold-freezing pain, which is also consistent with previous studies [17, 24, 38]. Therefore, our custom-built TGI device is valid and provided equivalent data to previous studies. In addition to these pain qualities, six other pain qualities were categorized into two components of TGI-induced pain. One consisted of hot-burning, aching, throbbing, and heavy qualities. Throbbing and aching were frequently reported by patients with postsurgical pain or a bone fracture [39], [40]. Furthermore, acute inflammation subsequent to such tissue damage induced throbbing and aching, and increased tissue temperatures leading to a hot sensation [41]. Considering these previous studies and our TGI experiment mainly induced hot-burning, it is not surprising that throbbing, aching, and hot-burning qualities should be classified into the same component. The other component consisted of cold-freezing, itching, electrical-shock, and numbness, which are common in neuropathic pain and often used for screening tests of neuropathic pain [14], [42]. Because the effects of TGI are related to the modulation of the nervous system, it is not surprising that cold-freezing, itching, electrical-shock, and numbness induced by TGI would be classified into the same component. The two components might have different neural mechanisms; however, we did not investigate these mechanisms in the present study. Future studies should clarify the neural mechanisms of each component by functional magnetic resonance imaging or electroencephalogram analyses.

Experiment 2 aimed to clarify the relationships between the qualities of TGI-induced pain and each type of neuropathic pain. From the results of the MCA and cross tabulation in Experiment 2, hot-burning, aching, cold-freezing, and numbness were highly related to central neuropathic pain (i.e. SCI and stroke patients) than to peripheral neuropathic pain (i.e. TN and PHN patients). These results indicated that TGI-induced pain qualities are more similar to central neuropathic pain than peripheral neuropathic pain. However, TGI-induced pain (e.g. burning pain, numbness) can also occur in peripheral neuropathy [37], but in the present study, the TGI-induced pain qualities were closer to those of central neuropathic pain than those of peripheral neuropathic pain. Because pain qualities are helpful to understand the underlying mechanism(s) of pain [43], our present results suggest that central neuropathic pain and TGI-induced pain share common neural substrates. The TGI phenomenon is an experience of misperception that actualizes synthetic pain via supraspinal involvement. Therefore, the supraspinal mechanism of TGI might be compatible with the pathological mechanism of post-stroke pain, which occurs due to lesions in the spino-thalamo-cortical sensory pathway (i.e. the medulla, pons, lenticulocapsular region, thalamus, and cerebral cortex) [44]. In addition to the supraspinal mechanism, TGI was reported to partially involve the spine [8], which might explain the compatible pain qualities between TGI-induced pain and SCI-related pain. In contrast to patients with central neuropathic pain, patients with peripheral neuropathic pain (TN and PHN) characteristically describe shooting and tender pain qualities [37], [45], which were not observed in our TGI paradigm. This indicates that the underlying mechanism of peripheral neuropathic pain is separate from that of TGI-induced pain. However, peripheral neuropathic pain (TN and PHN) also has spinal and supraspinal pathologies [46], [47], [48], suggesting it might share some pathological mechanisms with central neuropathic pain and explaining the partial similarity of pain qualities between peripheral and central neuropathic pain. Nevertheless, in the present study, TGI-induced pain quality was more similar to central neuropathic pain than peripheral neuropathic pain. These results might be supported by the idea that the pathological peripheral nervous system is the main pathway of peripheral neuropathic pain disease, and that the mechanisms of central neuropathic pain are more similar to the mechanism of TGI. However, the present study did not elucidate these common neural mechanisms, and future studies are needed.

Conclusion

TGI-induced pain qualities were similar to central neuropathic pain rather than peripheral neuropathic pain. Future studies should clarify the common mechanisms between TGI and central neuropathic pain.

Limitations

Several pain qualities (e.g. stabbing, piercing, cramping), which were common in patients with central neuropathic pain [15], [49] could not be observed in TGI paradigm. Although there are numerous phenotypes in central neuropathic pain diseases [15], [49], the TGI paradigm might not fully cover the phenotypes. However, our results are partially useful for investigating the origins of pathological pain. Future neurophysiological and neuropsychological studies should reveal the differences of phenotypes between central neuropathic pain and TGI-induced pain, indicating more precise underlying mechanisms of central neuropathic pain. Additionally, this study prioritized the clarification of varieties of TGI-induced pain qualities in a large number of subjects rather than conducting experiments with control conditions for the TGI (i.e., presentation of warm or cold bars alone). Furthermore, although we used a cold temperature of 16 °C to induce TGI, other studies have used temperatures ranging from 18 to 27 °C [17, 18, 27, 50–52]. These differences in temperatures between studies might have influenced the results and therefore, these results should be interpreted carefully. Regarding the assessment of pain quality, we used a different version of the questionnaire for Experiments 1 and 2 because of the different experimental and analytical procedures required, which might have influenced the results.