Applications of pain-related evoked potentials and short-latency somatosensory evoked potentials in acupuncture research: a narrative

Online Submissions: http://www.journaltcm.com J Tradit Chin Med 2015 October 15; 35(5): 606-612 info@journaltcm.com ISSN 0255-2922 2015 JTCM. All rights reserved. REVIEW TOPIC Applications of pain-related evoked potentials and short-latency somatosensory evoked potentials in acupuncture research: a narrative review Lin Chi, Ma Liangxiao, Zhu Shipeng, Hu Nijuan, Wang Pei, Zhang Peng, Qi Dandan, Hao Jie, Li Jing, Xin Siyuan, Zhu Jiang aa Lin Chi, Ma Liangxiao, Zhu Shipeng, Hu Nijuan, Wang Pei, Zhang Peng, Qi Dandan, Hao Jie, Li Jing, Xin Siyuan, Zhu Jiang, School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China Supported by the National Basic Research Program of China (973 Program)-the Effect of De Qi on Acupoint Specific Effect Based on Meridians and its Characteristics and Molecular Response Mechanisms (No. 2012CB518506); Research on Acupoint Specificity in Regulating Uterus (No. 2006- CB504503) and Research on Laws of Acupoint Effects (No. 2005CB523308); National Natural Science Foundation of China-Traditional Acupuncture Formula for Inducing Labor (Hegu-Sanyinjiao, LI4-SP6) Electro-acupuncture Parameter Optimization and Molecular Response Mechanisms (No. 30973793); and the Doctoral Program of Higher Education of Ministry Education of China-Research Based on Primary Dysmenorrhea on Electric Characteristics of Acupoints Which Were Different Ones on the Same Meridians or Similar Ones on the Different Meridians (No. 20090013110005) Correspondence to: Prof. Zhu Jiang, School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing 100029, China. jzhjzh@263.net Telephone: +86-10-64287719 Accepted: January 14, 2015 RESULTS: Thirty-seven articles were included in the review. Researchers usually use PREPs to study the analgesic effect of acupuncture, observe influential factors, or for mechanistic exploration. In the SLSEP studies, researchers focused on response characteristics of acupuncture, acupoint specificity, and influential factors of the treatment. There were some problems with the study design and conclusions. CONCLUSION: Researchers could use PREP and SLSEP to objectively validate the effects of acupuncture and explore its mechanisms using nerve electrophysiology. Further studies can benefit from observing more acupoints' effects using PREPs or SLSEPs and investigating the placebo effect of acupuncture. 2015 JTCM. All rights reserved. Key words: Acupuncture; Evoked potentials, somatosensory; Electrophysiology; Review Abstract OBJECTIVE: To review and discuss the Chinese and English literature on the use of pain-related evoked potentials (PREP) and short-latency somatosensory EP (SLSEP) in acupuncture research. METHODS: China National Knowledge Infrastructure Database and MEDLINE were searched for the following key words: acupuncture and PREP or SLSEP. INTRODUCTION Evoked potentials (EP) have developed to be a commonly applied technique in clinical neurology over the past half century. 1 EPs are electrical signals generated by the nervous system in response to sensory stimuli, such as auditory, visual, and somatosensory stimuli.1 The electrical signals evoked by somatosensory stimuli are called somatosensory EPs (SEPs), and are used to evaluate the conduction of neural structures along the somatosensory pathways. 1 In the 1970s, SEP methodology started to be used in acupuncture studies. Pain-related EPs (PREPs) and short-latency SEPs (SLSEPs) JTCM www. journaltcm. com 606

are two kinds of SEPs that are commonly used in acupuncture studies. PREPs are evoked by pain stimuli and are commonly used in pain-related studies. The later-latency components of PREPs (> 150 ms) are related to the sensation of pain. SLSEPs are conventional SEPs that are evoked by somatosensory stimuli whose intensity is adjusted to induce a visible twitch of the related muscle, but no pain. SLSEPs are widely used in clinical practice, because they are rarely influenced by consciousness and have explicit neural origins. This article reviews the application of PREPs and SLSEPs in clinical trials of acupuncture. METHODS An electronic database search of all fields was conducted on 6 May, 2014. For Chinese literature, the China National Knowledge Infrastructure Database (CNKI) was searched from 1980 to 2014. We used the following search terms: "(acupuncture) AND pain-related evoked potentials;" and "(acupuncture) AND short-latency somatosensory evoked potentials," which yielded 63 and 186 articles, respectively. For English literature, MEDLINE was searched from 1950 to 2014. We used the following search terms for PREP: "[(acupuncture) AND pain AND evoked potentials] AND English (language)" To prevent omissions, we repeated the search multiple times, replacing "evoked potentials" in the above search term with "brain activity," "evoked responses," "somatosensory processing," and "deactivation". In total, 263 articles related to PREP and acupuncture research were yielded. We used the following search terms for SLSEP: "[(acupuncture) AND somatosensory evoked potentials] AND English (language)" In total, 62 articles related to SLSEP and acupuncture research were yielded. A total of 574 articles resulted from the English language search. Articles were selected according to the following inclusion criteria: (a) using PREPs or SLSEPs to study the characteristics of acupuncture; and (b) carried out on humans. Excluded studies included those that: (a) used other neurophysiologic technologies such as brainstem auditory evoked potentials, functional magnetic resonance imaging, visual evoked potential, auditory evoked potentials, event related potentials, motor evoked potentials, or electroencephalogram; (b) were animal experimental studies; and (c) did not use PREP or SLSEP as outcome measures to assess the effect of a therapy to a disease. According to the above inclusion and exclusion criteria, we included 37 articles in this review. RESULTS Studies in the Chinese literature using PREPs Pain is subjective feeling that includes both experiences of intensity and emotion, and is often evaluated by visual analogy score (VAS). The development of PREPs has opened a new avenue for the study on pain. It is widely accepted that the later-latency components of PREPs can reflect sensation-discrimination processes of the brain in response to pain stimuli, such as locating stimuli and evaluating intensity. For example, the amplitude of the second positive wave of PREP (P2) is positively correlated with VAS scores. 2 For evaluating pain objectively, researchers started to use PREPs to investigate acupuncture analgesia. PREPs are often shown as an NP waveform, which is composed of a negative wave and a positive wave. The EP nomenclature states that a capital N or P represents a negative or positive wave, and a number after the letter represents its peak latency or its order of occurrence. For example, N20 represents a negative wave that appeared at 20 ms, and N2 represents the second negative wave. Because of different environments in different laboratories, the same components can have different latencies, which 3 leads to different names. For example, Xia et al blocked blood flow to isolate PREPs, which were evoked by posterior tibial nerve stimulation, and named the components P250-N350 according to the latencies. This means that the components are composed of a positive wave appearing at 250 ms and a negative wave appearing at 350 ms. Xia et al 4 used inverse averaging based on the computer average principle to separate the pure painful components of cerebral evoked potentials, which ranged from 170 to 240 ms and were different from those of Xia et al. 3 Researchers mainly used PREPs as an objective indicator of pain to verify the analgesic effect of acupuncture. Xia et al 5-12 reported that electro-acupuncture and auricular needling could both reduce the amplitude of PREPs, indicating an analgesic effect. Zeng et al 13 found that electro-acupuncture on both Hegu (LI 4) and non-acupoints could inhibit the amplitudes of the medium and late components of PREPs, and the effect of electro-acupuncture on Hegu (LI 4) was strikingly superior to that of electro-acupuncture on non-acupoints. This study suggested that acupoints had a more noticeable effect of analgesia than non-acupoints. Others observed that acupoints ipsilateral to the nerve stimulation were more effective at reducing the amplitude of PREPs than those contralateral to the nerve. 14 Some researchers who focused on how the acupuncture and suggestion affected PREPs, and found that acupuncture had analgesic effects, while suggestion did not play a major role in acupuncture analgesia. 15 According to the Chinese literature mentioned above, researchers mainly investigated how different interventions, acupuncture positions and suggestion affected acupuncture analgesia using PREPs. Studies in the Chinese literature using SLSEPs Researchers observed acupuncture efficacy using SLSEP and different interventions and acupuncture positions, which is similar to PREP studies. Xiong et al 16 found that both electro-acupuncture and tactile stimuli JTCM www. journaltcm. com 607

could reduce the amplitude of N20. However, they shortened and lengthened the latency of N13 (a negative wave that appeared at 13 ms). In a further study, it was found that different needling methods had different effects on SLSEPs. Tang et al 17 observed how depth of needling affected SLSEPs, and found there was no obvious difference in SLSEPs evoked by shallow or deep electro-acupuncture Lu et al 18 studied the effects of a simple pinprick or reinforcing and reducing acupuncture on N45 (a negative wave appearing at 45 ms) and P60 (a positive wave appearing at 60 ms) evoked by stimulating lower limb. The results demonstrated that the reinforcing method was opposite to that of the reducing method, because the methods shortened or lengthened the N45-P60 time, respectively. The study also demonstrated that the effect of the reinforcing method was the same as that of a simple pinprick, because both could lengthen the latency of N45. However, the reducing method had no effects on N45. Wei et al 19 compared an acupoint with a non-acupoint and demonstrated that electro-acupuncture Hegu (LI 4) could evoke SLSEPs, whose components were N1, the first negative wave, with a latency of 17-60 ms, and had lower amplitude than that evoked by electro-acupuncture at non-acupoints. In contrast to this study on N1, the N2 component evoked by Hegu (LI 4) had higher amplitude than that evoked by the non-acupoint. Kong et al 20 studied SLSEPs evoked by different acupoints, such as PC 6, LU 8, and HT 5, and found that the SLSEPs and brain electrical area mapping induced by the three points were similar. Therefore, it can be concluded that acupoints and non-acupoints affect SLSEPs differently. However, the effects of different acupoints on SLSEPs are similar. Studies in the English literature using PREPs There are also some English studies that report studies on acupuncture analgesia using PREPs. Zeng et al 21 found that electro-acupuncture acupoints significantly attenuated the amplitudes of P170 and N280, which were induced by painful median nerve stimulation. They also found that 2D topography exhibited decreased cortical activation between 120 and 296 ms in latency, and VAS values were simultaneously reduced. Therefore, electro-acupuncture acupoints have an analgesic effect. Winfried et al 22 reported that electro-acupuncture, compared with sham treatment, significantly decreased the amplitudes of PREPs evoked by electrical noxious stimulation in anesthetized subjects. To figure out the mechanisms underlying acupuncture analgesia, one study compared the analgesic effect of electro-acupuncture acupoints with those of three other kinds of interventions: hypnosis, morphine, and ketamine. 23 The study found that all four interventions could relieve pain. Hypnosis, acupuncture, and morphine were all effective for reducing the amplitudes of late-latency components related to cognition, but were not effective for reducing amplitudes of early-latency components related to the primary response of the cortex. This result suggests that the three methods induced analgesia at the latter stage of central nervous system stimulus processing. Meanwhile, ketamine had different effects and attenuated pain in the thalamo-cortical pathways. Studies in the English literature using SLSEPs In the English literature, researchers used SLSEPs to explore acupuncture interventions, acupuncture positions, and intensities. For acupuncture interventions, some researchers like Hsieh 24 reported that the latencies of N13, N20, and P25 evoked by stimulating the median nerve were unchanged when the interventions changed from electro-acupuncture, manual acupuncture, to no acupuncture. However, the amplitudes of P25 were the largest during 2-Hz electro-acupuncture, followed by manual acupuncture. During the session where no acupuncture was performed, P25 exhibited the smallest mean amplitudes. Kawashima 25 observed the effects of acupuncture and tactile skin stimulation on SLSEPs and found that acupuncture and tactile skin stimulation significantly suppressed the amplitudes of P22 and P40, and the suppression of P40 by acupuncture appeared to include different mechanisms from that of P22. Comparisons of acupoints and non-acupoints were investigated most frequently among SLSEP studies. One study found that the N1-P1 amplitudes induced by Hegu (LI 4) were lower than those induced by a non-acupoint, and the N2-P2 amplitudes of Hegu (LI 4) were higher than those of the non-acupoint. 26 Brain electrical area mapping changes also showed a similar effect on Hegu (LI 4). Abad-Alegría et al 27 observed the N1-P1 amplitudes affected by the acupoints Houxi (SI 3), Hegu (LI 4), and Shenmen (HT 7), and found that there were no statistical differences among them. They also compared acupoints and non-acupoints, and reported that the amplitudes of N1-P1 and the latency of N1 were different between the two. Abad-Alegría et al 28 also reported a significant increase in latency and decrease in amplitude of the peaks, which reflected that the primary cortical afferent occurred when Hegu (LI 4) was stimulated. There were no changes during non-acupoint stimulation. Yu et al 29 found that the amplitude of P150 evoked by magnetic stimulation on acupoints was greater than that of non-acupoints, suggesting that P150 might be a characteristic activation in response to acupoint afferents. Many studies have observed differences between acupoints and non-acupoints using SLSEP latencies and amplitudes, which suggests that the differences can be quantified. Some studies have focused on how different intensities of acupuncture stimuli applied to acupoints affect neurophysiological parameters of F-wave study and SL- SEPs. 30 The report concluded that the effect of acupunctural stimulation was closely related to the intensity of the stimulus applied and that the De Qi sensation JTCM www. journaltcm. com 608

was not required to obtain neurofunctional modifications. However, stimulations that went beyond De Qi produced greater effects. It is worth adding that some researchers bound SEPs with other techniques of neurophysiology during their studies. For example, Starr et al 31 observed electrophysiological characteristics during acupuncture-induced surgical analgesia and found there were no changes in electroencephalograms (EEG), SEP, and cognitive-evoked potentials. Others also used EEG, SEPs, visual evoked potentials (VEP), and auditory evoked potentials (AEP) to evaluate the effects of acupuncture and Qigong. 32 DISCUSSION In PREP studies, researchers were interested in objectively validating the analgesic effect of acupuncture. However, the literature published in Chinese and English reported from different perspectives. Chinese publications focus more on observing various factors of acupuncture on analgesia, such as needling in contralateral or ipsilateral acupoints or non-acupoints. English research is mostly interested in proving acupuncture analgesia and exploring its mechanisms. In SLSEP studies, researchers were interested in observing SLSEP while different interventions were applied to acupoints. They also focused on comparing acupoints and non-acupoints or comparing different acupoints, and the influence of acupuncture parameters. However, the influences of acupuncture parameters in the Chinese studies were about depth of needling and reinforcing-reducing methods, which are part of traditional acupuncture theory. In the English literature, researchers observed changes in SLSEPs while different intensities of acupuncture were used. Researchers also combined SL- SEPs and other electrophysiological techniques. When researchers focused on acupuncture analgesia, they used not only PREPs, but also SLSEPs. For example, Kumar et al 33 reported that the peak latency of N19 was significantly delayed in chronic pain patients when compared with the healthy volunteers. However, after the tenth treatment, the latency of N19 completely reverted to control values. Salar et al 34 also investigated acupuncture analgesia by SLSEPs. Electro-acupuncture and percutaneous electro-stimulation were observed to reduce the amplitude of SLSEPs. After 15 min, the administration of naloxone, an antagonist of morphine, in four subjects provoked a short but clear and immediate return of pain accompanied with a return of SLSEPs, implying that the analgesic mechanism of electro-acupuncture and percutaneous electro-stimulation might be similar to that of morphine. This result was consistent with that of another report. 23 Although both PREP and SLSEP were used in studies on acupuncture analgesia, the changes in these parameters have different meanings. PREPs can reflect the sensation-discrimination processes of the brain in response to pain stimuli, and can be used to objectively evaluate pain level. Therefore, a reduction in PREP amplitudes demonstrates pain relief. The nervous system generates SLSEPs was via the posterior column-medial lemniscus pathway, which delivers deep sensations and fine touch from hair follicles, joints, muscles, and tendons. Changes in SLSEPs suggest that nerve conduction in the posterior column-medial lemniscus pathway is affected. There have been several studies on comparisons between acupoints and non-acupoints. The conclusions are consistent that the effects of acupoints on PREPs or SLSEPs are different from those of non-acupoints. Wei et al 26 hypothesized that this may be because there are many nerve endings and muscle spindles at Hegu (LI 4), but fewer at non-acupoints. The activated nerve endings and muscle spindles produce additional needle sensations in subjects. Furthermore, additional sensations might be the reason acupoints have different effects on SLSEPs or PREPs from non-acupoints. Geng et al 35 similarly argued that the density of nerve clusters in acupoint areas is higher than that in non-acupoint areas, which might partly explain the differences. The study design of acupuncture studies tended to include five important aspects. First, in the nerve stimulation, most studies chose the median nerve, while some stimulated the posterior tibial nerve. The component N20-P25, belonging to the median nerve SLSEP was often observed because of its definite neural origination (parietal lobe). The most common component of PREP in studies was uncertain because the components' names differ from each other in the literature. However, those components of PREP are all late-latency ones (> 150 ms), such as N150, P170-N280, and P260. Researchers mainly used electrical (and sometimes magnetic) stimulation on nerves to evoke potentials. In acupuncture intervention, the most common acupoint in the studies was Hegu (LI 4), followed by Zusanli (ST 36), Shenmen (HT 7), and other acupoints on the large intestine meridian. The most common acupuncture technique was electro-acupuncture, with manual acupuncture tactile stimulation, and percutaneous electrical stimuli also being used. Most studies were carried out on healthy volunteers, who were dextral. Only a few trials recruited patients, such as patients with thyroid tumor or chronic pain. Researchers most frequently designed a study as a before-after study in the same individuals. However, randomized controlled trials were also used. Finally, researchers mainly observed the amplitudes and latencies of components. The magnitude of amplitude reflects the amount of synchronous discharging neurons in response to a stimulus. Peak latency was measured from the stimulus initiation point to the vertex of the reaction wave, which indicated the conduction of myelinated fibers in subjects. Many studies have reported that acupuncture can affect the amplitudes and latencies of JTCM www. journaltcm. com 609

SEPs. This might imply that the effect of acupuncture on the amount of synchronous discharging neurons was observed more commonly than the effects on conduction of myelinated fibers. These results might have something to do with the healthy volunteer subjects. The conclusions of PREP studies on acupuncture are consistent. Many studies found that acupuncture reduced the amplitudes of PREPs. The lower PREP amplitude was observed not only during but also after acupuncture, which implies a lasting analgesic effect of acupuncture. However, the conclusions of SLSEP studies on acupuncture are controversial. Some studies reported that acupuncture could affect SLSEPs, such as Xiong 16 and Kawashima et al 25 Some reported that acupuncture could not affect SLSEPs, such as Starr et al 31 and the Acupuncture Anesthesia Laboratory of Huashan Hospital of Shanghai First Medical College. 36 Others reported that acupuncture can only regulate patients' SLSEPs, such as Dong et al 37 and Kumar et al. 33 There were some problems identified in the literature, such as study design. These study problems mostly involved the choice of acupoints and the use of blinding methods. Further problems include the relationship between changes in SEP and clinical efficacy, and inconsistent nomenclature of SEP components. When observing how acupoints affect SEPs, there is no consensus on the choice of acupoints. Some researchers chose acupoints adjacent to the nerve stimulation, and some chose distant ones. Kawashima et al 25 found that needling distant acupoints contralateral to the nerve stimulation had no effect on SLSEPs. However, adjacent acupoints that were ipsilateral to the nerve stimulation could reduce SLSEP amplitudes. Another study also reported that electro-acupuncture ipsilateral acupoints reduced SEP amplitudes more significantly than electro-acupuncture contralateral acupoints. 14 Therefore, some researchers chose adjacent acupoints during studies because they might change SEPs. However, other studies suggested that SEPs elicited by two kinds of electrical stimulation simultaneously applied to either adjacent or the same peripheral nerve created mutual interference. 31 Therefore, bilateral Zusanli (ST 36) were chosen that are distant to the median nerve stimulation at the right wrist region. At present, no studies have investigated possible mutual interference of adjacent acupoints and whether adjacent or distant acupoints are best to choose. Throughout the literature, few trials used blinding methods. The medium and late components of SEPs can be influenced by psychological factors, so blinding is necessary to reduce possible mutual interference. SEP records may also be influenced by recorders' subjective factors. Therefore, it is necessary to blind recorders to ensure objective measurement. Changes in PREPs can reflect analgesic effects of acupuncture. However, it is unclear whether SLSEPs can reflect the clinical effects of acupuncture. One study demonstrated that a greater intensity of acupuncture led to greater changes in SLSEP amplitudes and latencies. 30 This study was carried out on healthy volunteers, so it did not suggest that more significant changes in SLSEP had anything to do with better clinical effects. Many studies that used PREPs and SLSEPs to investigate the mechanism of acupuncture were also carried on healthy subjects. Therefore, conclusions should be cautiously drawn from these studies, and changes in SEP may not equate with clinical effects. In the PREP studies, acupuncture was found to reduce the amplitudes of the components, but the inhibited components varied among studies. 13-15, 21-23 This phenomenon is probably because of different methods used in laboratories that lead to different latencies of the same component. The PREP components are named according to their latencies, so the same component might have different names. This problem makes it difficult to compare results among studies. If names of components were consistent, researchers could figure out how many pain-related components exist and the differences between them. This problem also exists in SLSEP studies. Inconsistent nomenclature of SEP components needs to be standardized. Further studies should incorporate two important aspects. As mentioned before, Hegu (LI 4) was the most common acupoint chosen for studies. 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