Prog Neurobiol. 2008 Aug;85(4):355-75. Epub 2008 Jun 5.
Neural mechanism underlying acupuncture analgesia.
Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. firstname.lastname@example.org
Acupuncture has been accepted to effectively treat chronic pain by inserting needles into the specific “acupuncture points” (acupoints) on the patient’s body. During the last decades, our understanding of how the brain processes acupuncture analgesia has undergone considerable development. Acupuncture analgesia is manifested only when the intricate feeling (soreness, numbness, heaviness and distension) of acupuncture in patients occurs following acupuncture manipulation. Manual acupuncture (MA) is the insertion of an acupuncture needle into acupoint followed by the twisting of the needle up and down by hand. In MA, all types of afferent fibers (Abeta, Adelta and C) are activated. In electrical acupuncture (EA), a stimulating current via the inserted needle is delivered to acupoints. Electrical current intense enough to excite Abeta- and part of Adelta-fibers can induce an analgesic effect. Acupuncture signals ascend mainly through the spinal ventrolateral funiculus to the brain. Many brain nuclei composing a complicated network are involved in processing acupuncture analgesia, including the nucleus raphe magnus (NRM), periaqueductal grey (PAG), locus coeruleus, arcuate nucleus (Arc), preoptic area, nucleus submedius, habenular nucleus, accumbens nucleus, caudate nucleus, septal area, amygdale, etc. Acupuncture analgesia is essentially a manifestation of integrative processes at different levels in the CNS between afferent impulses from pain regions and impulses from acupoints. In the last decade, profound studies on neural mechanisms underlying acupuncture analgesia predominately focus on cellular and molecular substrate and functional brain imaging and have developed rapidly. Diverse signal molecules contribute to mediating acupuncture analgesia, such as opioid peptides (mu-, delta- and kappa-receptors), glutamate (NMDA and AMPA/KA receptors), 5-hydroxytryptamine, and cholecystokinin octapeptide. Among these, the opioid peptides and their receptors in Arc-PAG-NRM-spinal dorsal horn pathway play a pivotal role in mediating acupuncture analgesia. The release of opioid peptides evoked by electroacupuncture is frequency-dependent. EA at 2 and 100Hz produces release of enkephalin and dynorphin in the spinal cord, respectively. CCK-8 antagonizes acupuncture analgesia. The individual differences of acupuncture analgesia are associated with inherited genetic factors and the density of CCK receptors. The brain regions associated with acupuncture analgesia identified in animal experiments were confirmed and further explored in the human brain by means of functional imaging. EA analgesia is likely associated with its counter-regulation to spinal glial activation. PTX-sesntive Gi/o protein- and MAP kinase-mediated signal pathways as well as the downstream events NF-kappaB, c-fos and c-jun play important roles in EA analgesia.
Zhen Ci Yan Jiu. 1996;21(1):4-11.
The modulation of cerebral cortex and subcortical nuclei on NRM and their role in acupuncture analgesia.
[Article in Chinese]
Institute of Acupuncture and Moxibustion, China Academy of Traditional Chinese Medicine, Beijing.
The vast research have demonstrated that the acupuncture analgesia is effected through a physiological mechanism brought about by the nervous system, particularly the central nervous system. We combined the acupuncture effects and theory of channels and collaterals with the new advance of pain neurophysiology, and centred attention on nucleus raphe magnus (NRM), that is one of the origins of the important descending inhibitory pathways of the intrinsic analgesic systems in brain. The unit discharges of NRM neurons and their nociceptors/ph responses were recorded extracellularly with glass microelectrode at 1495 neurons on 634 wastar rats. The modulation of cerebral cortex, the head of N. caudatum (NCa), N. Accumbens (N. Ac), N lateral habenular (NHa) and Periaquaeductal gray matter (PAG) on NRM and their role in acupuncture analgesia were studied by central locational stimulation, lesion and microinjection. The result were as follows: 1. The most NRM neurons could respond to noxious stimulation of tail tip with increasing or decreasing firing rate. Electroacupuncture (EA) at “Zusanli” could activate the NRM neuron, increasing discharges, and inhibit their nociceptive responses, producing analgesia. 2. The activity of NRM neuron was modulated by PAG, NAc, and NCa. Stimulation at one of them can activate neuron of NRM, increasing firing rate, and induce analgesia. When the lesion or microinjection naloxone were made in PAG, NAc or NCa, EA analgesia could be weakened or lost, even the nociceptive responses might be increased. It is suggest that the nuclei participated in EA analgesia with their endogenous opiate like substance, and were playing an important role. It is also indicated that the electroacupuncture was used on the patients with some nuclei lesion or pathological changes should be careful to avoid making patients feel more painful. 3. Somatosensory area II (Sm II) of cerebral cortex participated in EA analgesia. The analgesic effects of EA at “Zusanli” were reduced after lesion of Sm II. The nociceptive responses could be inhibited by stimulation of Sm II. We have further demonstrated that analgesic effects of Sm II stimulation were achieved by the modulation of Sm II on NRM, via NAc and NHa closely related to limbic-midbrain system, and with NRM descending inhibitory pathways through dorsal lateral fasciculus (DLF) in the level of spinal cord. 4. The sensorimotor area (SM) of cerebral cortex seems was not necessary structure for EA analgesia. Either of hindlimb areas or larger range of bilateral SM were resected, the analgesic effects of EA at “Zusanli” were not obviously influenced. The stimulation of somatosensory area I (Sm I) of SM could inhibit the nociceptive responses of NRM neurons. It was also demonstrated the Sm I could modulate NRM by mediation of NCa of extrapyramidal system enhancing EA analgesia. Stimulation of Sm I could directly inhibit the nociceptive responses through pyramidal system in the level of spinal cord, producing analgesia. But the information of electroacupuncture was noxious stimulation, so it could be also inhibited by Sm I stimulation, playing an antagonism to EA analgesia. Thus when patient’s emotion was very nervous or physical exercise was very strong, EA analgesic effects would be decreased. Therefore, in order to guarantee EA analgesic effects, it is necessary that patients should take a rest and calm down before electroacupuncture. The contrary action between pyramidal and extrapyramidal systems in EA analgesia may be the one of mechanisms of that EA analgesia to be not full and changeful.
Acupunct Electrother Res. 2007;32(3-4):179-93.
Neuronal specificity of needling acupoints at same meridian: a control functional magnetic resonance imaging study with electroacupuncture.
Zhang JH, Cao XD, Lie J, Tang WJ, Liu HQ, Fenga XY.
Department of Radiology, Huashan Hospital, Shanghai, China.
The purpose of this study was to investigate the neuronal specificity of needling acupoints at same meridian by functional Magnetic Resonance Imaging (fMRI). The selected acupoints GB34 (Yanglinquan) and GB39 (Xuanzhong) were at the same gallbladder meridian based on traditional Chinese medicine. In our study we devise three distinct EA (electroacupuncture) manipulations: real EA (deep needling at acupoints), sham EA (deep needling at no-meridian points) and shallow EA (subcutaneous needling at acupoints). Twelve healthy volunteers with right-handiness were enrolled and received three different EA manipulations in counter-balanced orders. DeQi scores were used to evaluate the degree of needling sensation. We found real EA can induce significant stronger needling sensation than sham EA and shallow EA. Multisubjects group mean analysis showed that pain-related cortex including primary and secondary somatosensory cortex (SI and S II), anterior cingulated cortex (ACC), insula were involved in three EA stimulation. Bilateral activation of prefrontal gyrus and occipital cortex were exclusively found in real EA. Deactivation over the rostral segment of ACC was also shown in real and shallow EA. Further paired two difference analysis indicated that real EA induced higher activation than sham EA over bilateral prefrontal gyrus, right-side occipital gyrus and deactivation over the rostral segment of ACC. In the comparing with real EA versus shallow EA, there was right-side activation over the SI, S II, motor cortex, ACC, insula, thalamus, hippocampus, occipital cortex, and cerebellum; also activation over bilateral prefrontal gyrus, caudate and pons. Although no significant activation was found over periaqueductal gray (PAG), further analysis showed the mean and maximal signal changes were different under three EA manipulations. We concluded that EA at analgesic acupoints of same meridian maybe involved the pain-related neuromatrix especially the hypothalamus-limbic system; deep EA at meridian points could elicit stronger needling sensation and modulate the pain-related neuromatrix more effectively than EA at nonmeridian points or shallow EA at meridian points.
Chin J Integr Med. 2007 Mar;13(1):10-6.
Study on the regulatory effect of electro-acupuncture on hegu point (LI4) in cerebral response with functional magnetic resonance imaging.
Wang W, Liu L, Zhi X, Huang JB, Liu DX, Wang H, Kong XQ, Xu HB.
Radiology Department, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
OBJECTIVE: To study, through blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI), the cerebral activated areas evoked by electro-acupuncturing (EA) the right Hegu point (L14) or non-acupoint points on the face, and through comparing their similarities and differences, to speculate on the specific cerebral areas activated by stimulating L14, for exploring the mechanism of its effect in potential clinical application. METHODS: EA was applied at volunteers’ right L14 (of 9 subjects in the L14 group) and facial non-acupoint points (of 5 subjects in the control group), and whole brain 3-dimensional T1 anatomical imaging of high resolution 1 x 1 x 1 mm(3) used was performed with clustered stimulatory mode adopted by BOLD fMRI. Pretreatment and statistical t-test were conducted on the data by SPM2 software, then the statistical parameters were superimposed to the 3-dimensional anatomical imaging. RESULTS: Data from 3 testees of the 9 subjects in the L14 group were given up eventually because they were unfit to the demand due to different causes such as movement of patients’ location or machinery factors. Statistical analysis showed that signal activation or deactivation was found in multiple cerebral areas in 6 subjects of L14 group and 5 subjects of the control group (P<0.01). In the L14 group, the areas which showed signal activation were: midline nuclear group of thalamus, left supra marginal gyrus, left supra temporal gyrus, right precuneous lobe, bilateral temporal pole, left precentral gyrus and left cerebellum; those which showed signal deactivation were: bilateral hippocampus, parahippocampal gyrus, amygdala body area, rostral side/ audal side of cingulate gyrus, prefrontal lobe and occipital lobe as well as left infratemporal gyrus. In the control group, areas which showed signal activation were: bilateral frontal lobe, postcentral gyrus, Reil’s island lobe, primary somato-sensory cortex, cingulate gyrus, superior temporal gyrus, occipital cuneiform gyrus and/or precuneus gyrus and right brainstem; and the area that showed deactivation was left median frontal lobe. CONCLUSION: The effects of EA L14 in regulating cerebral activities could be displayed and recorded through BOLD fMRI, the distribution of signally deactivated area evoked by EA L14 was similar to the known distribution of anatomical orientation of pain in brain, and closely related to the anatomic structure of limbic system, which areas are possibly the acupuncture analgesic effect’s cerebral regulating area. Furthermore, activated portion of left central anterior gyrus, which represent the movement of oral facial muscles, and the activated portion of cerebellum are possibly related with the effect of using EA L14 in treating facial palsy and facial muscle spasm. As for the mechanism of signal deactivation of cerebral activities exhibited in the present study that is unable to be elucidated, it awaits for further research.
Neuroimage. 2002 Aug;16(4):1028-37.
Neuronal specificity of acupuncture response: a fMRI study with electroacupuncture.
Wu MT, Sheen JM, Chuang KH, Yang P, Chin SL, Tsai CY, Chen CJ, Liao JR, Lai PH, Chu KA, Pan HB, Yang CF.
Department of Radiology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, Republic of China.
Recently, neuronal correlates of acupuncture stimulation in human brain have been investigated by functional neuroimaging. The preliminary findings suggest that acupuncture at analgesic points involves the pain-related neuromatrix and may have acupoint-brain correlation. Although multiple models of control stimulations have been applied to address the specificity of the needling effect clinically, their impacts have not been evaluated by functional neuroimaging. With the advantage of objective parameter setting, electroacupuncture (EA) was used in this study to devise three distinct controls for real EA, i.e., mock EA (no stimulation), minimal EA (superficial and light stimulation), and sham EA (same stimulation as real EA) applied at nonmeridian points. Fifteen healthy volunteers received real EA at analgesic point Gallbladder 34 (Yanglinquan), sham EA, and one of either mock EA or minimal EA over the left leg in counter-balanced orders. Multisubject analysis showed that sham EA and real EA both activated the reported distributed pain neuromatrix. However, real EA elicited significantly higher activation than sham EA over the hypothalamus and primary somatosensory-motor cortex and deactivation over the rostral segment of anterior cingulate cortex. In the comparison of minimal EA versus mock EA, minimal EA elicited significantly higher activation over the medial occipital cortex. Single-subject analysis showed that superior temporal gyrus (encompassing the auditory cortex) and medial occipital cortex (encompassing the visual cortex) frequently respond to minimal EA, sham EA, or real EA. We concluded that the hypothalamus-limbic system was significantly modulated by EA at acupoints rather than at nonmeridian points, while visual and auditory cortical activation was not a specific effect of treatment-relevant acupoints and required further investigation of the underlying neurophysiological mechanisms.
Can J Vet Res. 2003 May;67(2):94-101.
Different central manifestations in response to electroacupuncture at analgesic and nonanalgesic acupoints in rats: a manganese-enhanced functional magnetic resonance imaging study.
Chiu JH, Chung MS, Cheng HC, Yeh TC, Hsieh JC, Chang CY, Kuo WY, Cheng H, Ho LT.
Institute of Traditional Medicine, National Yang-Ming University, Number 155, Section 2, Li-Nong Street, Peitou, Taipei, 112 Taiwan, Republic of China. email@example.com
Acupuncture analgesia is an important issue in veterinary medicine. This study was designed to elucidate central modulation effects in response to electroacupuncture (EA) at different acupoints. Manganese-enhanced functional magnetic resonance imaging was performed in Sprague-Dawley rats after sham acupuncture, sham EA, or true EA at somatic acupoints. The acupoints were divided into 3 groups: group 1, analgesic acupoints commonly used for pain relief, such as Hegu (LI 4); group 2, nonanalgesic acupoints rarely used for analgesic effect such as Neiguan (PC 6); and group 3, acupoints occasionally used for analgesia, such as Zusanli (ST 36). Image acquisition was performed on a 1.5-T superconductive clinical scanner with a circular polarized extremity coil. The results showed that there was no neural activation caused by EA at a true acupoint with shallow needling and no electric current (sham acupuncture). When EA at a true acupoint was applied with true needling but no electric current (sham EA), there was only a slight increase in brain activity at the hypothalamus; when EA was applied at a true acupoint with true needling and an electric current (true EA), the primary response at the hypothalamus was enhanced. Also, there was a tendency for the early activation of pain-modulation areas to be prominent after EA at analgesic acupoints as compared with nonanalgesic acupoints. In conclusion, understanding the linkage between peripheral acupoint stimulation and central neural pathways provides not only an evidence-based approach for veterinary acupuncture but also a useful guide for clinical applications of acupuncture.
Am J Vet Res. 2001 Feb;62(2):178-82.
Electroacupuncture-induced neural activation detected by the use of manganese enhanced functional magnetic resonance imaging in rabbits.
Chiu JH, Cheng HC, Tai CH, Hsieh JC, Yeh TC, Cheng H, Lin JG, Ho LT.
Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China.
OBJECTIVE: To investigate the effects of acupuncture on neural activity detected by use of manganese-enhanced functional magnetic resonance imaging (fMRI) and elucidate the relationship between somatic acupoint stimulation and brain activation. ANIMALS: 40 New Zealand White rabbits. PROCEDURE: Manganese-enhanced fMRI was performed in anesthetized rabbits manipulated with electroacupuncture (EA) on Zusanli (ST-36) and Yanglingquan (GB-34) acupoints. Image acquisition was performed on a 1.5T superconductive clinical scanner with a circular polarized extremity coil. T1-weighted images were acquired sequentially as follows: baseline, after mannitol injection, after manganese infusion, and 5 and 20 minutes after initiation of EA. RESULTS: Changes in focal neural activity were detected by use of manganese-enhanced fMRI. Stimulation on Zusanli (ST-36) for 5 minutes resulted in activation of the hippocampus, whereas stimulation on Yanglingquan (GB-34) resulted in activation of the hypothalamus, insula, and motor cortex. Activation became less specific after 20 minutes of EA. Furthermore, stimulation on ipsilateral acupoints led to bilateral brain activation. CONCLUSIONS AND CLINICAL RELEVANCE: Each acupoint has a corresponding cerebral linkage, and stimulation on these points resulted in time-dependent neural activation. Understanding the linkage between peripheral acupoint stimulation and central neural pathways may provide a useful guide for clinical applications of acupuncture.