Mechanism of Action

Acupuncture’s mechanism of action is being investigated from a number of different angles. I outline a few trajectories here, but please let me know if you have found other approaches that have shown scientific merit.

This page will be augmented by my own interpretation of the current research, but for now it’s a link compendium. More interesting stuff on the way!

Overview

Image courtesy Topnews.in

Neuroscience of Acupuncture

Leading Researchers

fMRI and PET Studies

Electroacupuncture Studies

Biology of Connective Tissue, Fascia, Extracellular Matrix: Acupuncture’s Effect

Leading Researchers

Studies

Endocrinology: Acupuncture’s Effect

Leading Researchers

Studies

Sham/ Placebo Control/ Study Design Debate

Overview:

Vitaly Napadow, Andrew Ahn, John Longhurst, Lixing Lao, Elisabet Stener-Victorin, Richard Harris, Helene M Langevin (2008) The status and future of acupuncture mechanism research, 861-9. In Journal of alternative and complementary medicine (New York, N.Y.) 14 (7).

Shu-Ming Wang, MD, Richard E. Harris, PhD, Yuan-Chi Lin, MD, MPH, and Tong-Joo Gan, MD, FRCA, MHS (June 2013) Acupuncture in 21st Century Anesthesia: Is There a Needle in the Haystack? 1356-1359.  Anesthestia & Analgesia. 116 (6).

Neurobiological Mechanisms of Acupuncture: 2013 issue of Evidence-Based Complementary and Alternative Medicine. Guest Editors: Lijun Bai, Richard E. Harris, Jian Kong, Lixing Lao, Vitaly Napadow, and Baixiao Zhao.

Hugh MacPherson, Richard Hammerschlag.  Acupuncture and the Emerging Evidence Base: Contrived Controversy and Rational Debate (full text)  Journal of Acupuncture and Meridian Studies. Aug 2012, Vol. 5, No. 4: 141-147
EXCERPT FROM THIS ARTICLE:

Physiology of acupuncture

Understanding the physiological basis of acupuncture is a long-standing goal of laboratories and clinics both East and West. Such research appears to have taken two main paths: the search for biochemical and physiologic endpoints (“biomarkers”) whose concentrations and/or activity change in response to needling, and the exploration of how the biomedical model can describe and explain phenomena based in the traditional paradigm of acupuncture. While each path is notable for its progress and promise, each has been constrained by its methods and models.

The first of these research paths has led to numerous identifications of acupuncture-related biomarkers, including antinociceptive endogenous opioids 3334, immune system markers 3536, cardiovascular activity [37], gastrointestinal function [38] and fMRI-detected brain activity [39]. Biomarker outcomes, however, are more revealing of correlations (i.e. when needling occurs, changes can be detected) than mechanisms. Reviews of acupuncture from China 4041 and the West 4243 continue to use the overarching term ‘mechanism’ but focus almost entirely on “correlates.” For example, while the call for “a complete and plausible mechanism through which to understand its [acupuncture’s] clinical effects” is representative of a generally held goal, the major focus of most reviews is on downstream biomarkers with little attention to the sequence of needling-initiated steps that result in the biomarker changes. Such a stepwise approach was followed to a limited extent to map pathways related to acupuncture-induced analgesia [33] and cardiovascular regulation [43].

The second research path, more directly aimed at defining mechanisms, has involved a search for anatomical, biochemical and physiological bases of acupuncture phenomena, including those associated with acupuncture points and meridians. Questions guiding these research efforts include: what is an acupuncture point; what does the needle initially stimulate; and, what local and systemic changes occur in response to needling? And, do meridians have a physical basis and what is the nature of the ‘acu-signals’ they carry?

This general approach holds considerable promise but a cautionary note seems warranted: the frequently stated conviction that a ‘neurocentric’ model can best explain acupuncture’s actions may prove too limited a perspective. For example, as recently opined, “In this view [the neural hypothesis], meridians and their associated acupoints would be considered as simply road maps that help guide the practitioner where to stimulate to achieve the best clinical results. However, it is the stimulation of the underlying neural pathways that can account for the physiological effects and clinical responses to acupuncture in patients” [44]. For the present review, evidence in support of the neural hypothesis will be presented, where feasible, together with data supportive of the emerging view of loose connective tissue (fascia) as an alternative biomedical underpinning of acupuncture’s traditional landmarks.

While no unique anatomical structure, e.g., a specialized type of nerve ending, has been identified at cutaneous sites corresponding to acupuncture points, several studies have described an association of known morphological structures with acupoints. A large proportion of traditional acupuncture points have been identified as sites at which underlying nerve-vessel bundles wrapped in a loose sheath of connective tissue penetrate the fascia to reach the outer dermal layers 4546. A subsequent study of 24 acupoints on 6 meridians demonstrated a high correspondence between the sites of acupuncture points and the location of loose connective tissue planes [47].

Acupuncture point structures per se have been reported in studies utilizing high-intensity ultrasound, with ovoid images proposed as acupoints localized in connective tissue 4849. In light of the several lines of evidence suggesting a connective tissue basis for acupoints, the oft-cited findings that injection of local anesthetic into an acupoint blocks responsiveness of the point to needle stimulation 5051 should be re-examined by testing for effects of local anesthetics on connective tissue function.

On the broad spectrum of research aimed at the characterization of acupoints, electrodermal activity (EDA) continues as one of the more frequently examined and controversial endpoints. Becker’s use of a 36-electrode square grid, revealing acupoints as the summits of individually contoured conductivity fields, remains one of the seminal contributions to this field[52]. Recent reviews have highlighted the experimental and physiological confounders to such measurements [53] and have systematically evaluated studies comparing EDA at acupoints relative to non-acupoint sites in healthy volunteers [54]. In this latter review, five of nine studies that met inclusion criteria for design and reporting showed a positive association for acupuncture points as sites of lower electrical resistance and impedance. The relation of acupoint EDA to pathology is described in a recent narrative review [55]. Among the included trials was a blinded study in which EDA at auricular acupuncture points distinguished patients with recent or prior cardiopathology from healthy controls [56].

The abundance of sensory nerve endings in the skin, the experimental recording of neural activity following needle insertion, and numerous correlations between neuromodulatory endogenous opioids and acupuncture-induced pain modulation were major factors that led researchers to develop elegant models depicting pathways of acupuncture analgesia through the peripheral and central nervous systems 3334. Such research had a strong influence on the thinking that acupuncture effects in general, not just its analgesic activity, could be mapped onto the nervous system 4457. Striking confirmation of neural involvement in acupuncture stems from medical imaging research 3958. Patterns of fMRI and PET signals have been detected following acupuncture that are distinct from patterns evoked by simple sensory stimuli or expectation (placebo) 5960. Nonetheless, while detection of brain activity consequent to needle stimulation reveals the brain as an endogenous monitor of acupuncture actions, it does not necessarily follow that neural activity, including sensory nerve ending activation, is the initiator of these physiological events.

As mentioned above, considerable evidence has accumulated for an interstitial connective tissue-based system as an additional or alternative mediator of acupuncture activity. Indications of superficial fascia as the initial ‘response element’ to needle stimulation include an apparent wrapping of collagen fibers around the needle that may explain the ‘needle grasp’ phenomenon of acupuncture practice [61], as well as a weakening of mechanical and clinical responses to needling (in rats) following acupoint injection of collagenase [62]. Observations that needling also induces local changes in blood flow[63], which may result from acupuncture-related peripheral increases in nitric oxide 6465, and the proposed role of needling-induced peripheral release of ATP as an intermediary signal molecule between connective tissue and sensory nerve endings 6667 await future research to clarify the sequence of events underlying the transduction of acupuncture stimulation to acupuncture signaling.

In summary, the neural hypothesis of meridians rests in large part on observations that a number of key acupoints and significant linear portions of meridians overlie major peripheral nerves [44]. Additionally, an intriguing model explains the subjective phenomenon of “propagated sensations along the meridians” as a resultant of neuronal connectivity in the spinal cord during the relay of presumed “acu-signals” to the brain [68].

The connective tissue hypothesis of meridians, for its part, is based on the observation that traditional pathways of acupuncture meridians correspond to ultrasound images of connective tissue planes [47]. Moreover, such bands of meridian-oriented collagenous structures are associated with lower electrical impedance [69], as was also detected in seven of nine studies of electrodermal activity along acupuncture meridians at both subcutaneous and intermuscular depths[54]. The proposal that triple-stranded collagen fibers support a rapid flow of hydrogen ions (protons) along water molecules bound to the fibers’ outer shell has intriguing implications for acupuncture-related information signaling [70]. Further elucidation of the mechanotransduction events by which needling perturbs connective tissue elements and initiates signaling is a key area of acupuncture mechanism research 7172.

Further questioning of the primacy of the neural model comes from proponents of the Bonghan intravascular system (primo vessels) 7374 and from those who favor a biophysical model in which endogenously generated electromagnetic fields form standing waves that comprise an energetic representation of meridians 7576.

In summary, while no anatomical or biochemical features have yet been unambiguously identified that uniquely identify acupuncture point sites and meridians, the balance of evidence favors quantitative differences in electrodermal properties between acupoints and surrounding skin 5455. In addition, evidence of correlations between loose connective tissue anatomy and the acupuncture system is emerging as a viable alternative to the prevailing neurobiological models 6269. A cautionary note regarding translational research bridging physiology and efficacy of acupuncture is that lack of a clear understanding of the events initiated by acupuncture needle insertion confounds the design of an appropriate sham acupuncture procedure for clinical trials 7778.

Neuroscience of Acupuncture:

Leaders in neuroscience research of acupuncture:

Lijun Bai, PhD: The Key Laboratory of Biomedical Information Engineering, Ministry of Education, Department of Biomedical Engineering, School of Life Science and Technology, Xi’an Jiaotong University, China

Lijun Bai and Lixing Lao. Neurobiological Foundations of Acupuncture: The Relevance and Future Prospect Based on Neuroimaging Evidence, Evidence Based Complementary and Alternative Medicine: Neurobiological Mechanisms of Acupuncture. Volume 2013 (2013).

Lijun Bai, Jie Tian, Chongguang Zhong, Ting Xue, Youbo you, Zhenyu Liu, Peng Chen, Qiyong Gong, Lin Ai, Wei Qin, Jianping Dai, and Yijun Liu. Acupuncture modulates temporal neural responses in wide brain networks: evidence from fMRI studyMol Pain. 2010; 6: 73.

Yin Jiang, Hong Wang, Zhenyu Liu, Yuru Dong, Yue Dong, Xiaohui Xiang, Lijun Bai, Jie Tian, Liuzhen Wu, Jisheng Han, and Cailian Cui. Manipulation of and Sustained Effects on the Human Brain Induced by Different Modalities of Acupuncture: An fMRI Study (full text). PLoS One. 2013; 8(6): e66815.

Florian Beissner, PhD : Research Fellow in Radiology at Harvard Medical School, Research Fellow at Massachusetts General Hospital, Department of Radiology, MGH

F Beissner (2011)  fMRI studies of acupuncture mechanisms – a critique. (pdf) Focus on Alternative and Complementary Therapies. 16: 1. 3-11.

Florian Beissner, Irene Marzolff (2012) Investigation of Acupuncture Sensation Patterns under Sensory Deprivation Using a Geographic Information System. (full text) Evidence-based complementary and alternative medicine: eCAM. 2012: 591304.

F Beissner, Ralf Deichmann, Christian Henke, KJ Bär (2012) Acupuncture- Deep pain with an autonomic dimension? NeuroImage. 60:1. 653-660.

Richard Harris, PhD: University of Michigan, Assistant Professor in the Department of Anesthesiology and Research Assistant Professor in the Department of Internal Medicine.

Harris RE, Zubieta JK, Scott DJ, Napadow V, Gracely RH, Clauw DJ. Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs). Neuroimage. 2009;47(3):1077-1085.

JIan Kong, MD: Assistant Professor at Harvard Medical School, Associate Researcher at Massachusetts General Hospital, Department of Psychiatry, MGH

Chae, Y., Chang, D. S., Lee, S. H., Jung, W. M., Lee, I. S., Jackson, S., … & Wallraven, C. (2013). Inserting needles into the body: a meta-analysis of brain activity associated with acupuncture needle stimulation. The Journal of Pain.

Lixing Lao, MD, PhD, LAc: Director of the Traditional Chinese Medicine Research Program at the Center for Integrative Medicine (CIM), University of Maryland, Baltimore (UMB), School of Medicine, Md, USA. Guest Professor at the Shanghai University of Traditional Chinese Medicine, Shanghai, China, and the Beijing University of Chinese Medicine.

[biographical] Fan AY. Dialogue with Dr. Lixing Lao: from a factory electrician to an international scholar of Chinese medicine. (pdf) J Integr Med. 2013; 11(4): 278-284.

Li A, Lao L, Wang Y, et al. Electroacupuncture activates corticotrophin-releasing hormone containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation. (full text) BMC Complement Altern Med. 2008;8:20.

Zhang RX, Lao L, Wang X, et al. Electroacupuncture attenuates inflammation in a rat model. JA – J Altern.C. 2005;11(1):135-142

Peng Li, MD, LAc: Project Scientist III, Medicine; School of Medicine, University of California Irvine

Li P, Longhurst JC. Neural mechanism of electroacupuncture’s hypotensive effects. (full text) Auton Neurosci. 2010;157:24–30

John Longhurst, MD, PhD: Professor of Medicine at the School of Medicine, University of California Irvine. Director, Susan Samueli Center for Integrative Medicine, UC Irvine School of Medicine.

Longhurst JC. Defining meridians: a modern basis of understanding. J Acupunct Meridian Stud. 2010;3:67–74

Zhou W, Longhurst JC. Neuroendocrine mechanisms of acupuncture in the treatment of hypertension. (full text) Evid Based Complement Alternat Med. 2012;2012:878673.

Seung-Nam Kim:  Kyung Hee College of Oriental Medicine, Seoul, South Korea

Seung-Tae Kim, Ah-Reum Doo, Seung-Nam Kim, Song-Yi Kim, Yoon Young Kim, Jang-Hyun Kim, Hyejung Lee, Chang Shik Yin, Hi-Joon Park. Acupuncture suppresses kainic acid-induced neuronal death and inflammatory events in mouse hippocampusThe Journal of Physiological Sciences.07/2012; 62(5):377-83.

Kim SKBae HAcupuncture and immune modulation. Auton Neurosci. 2010 Oct 28;157(1-2):38-41.

Vitaly Napadow, PhD, LAc: Harvard Medical School, Assistant Professor, Dept of Radiology

Napadow V, Liu J, Li M, et al. Somatosensory cortical plasticity in carpal tunnel syndrome
treated by acupuncture. Hum Brain Mapp. 2006.

Napadow V, Kettner N, Liu J, et al. Hypothalamus and amygdala response to acupuncture stimuli in carpal tunnel syndrome. (full text) Pain. 2007.

Dhond RP, Kettner N, Napadow V. Neuroimaging acupuncture effects in the human brain. J Altern Complement Med.2007;13:603–616

Baixiao Zhao, MD, PhD: Associate Dean of the College of Acupuncture at Beijing University of TCM

Abdi H, Zhao B, Darbandi M, Ghayour-Mobarhan M, Tavallaie S, Rahsepar AA, Parizadeh SM, Safariyan M, Nemati M, Mohammadi M, Abbasi-Parizad P,Darbandi S, Akhlaghi S, Ferns GA. The effects of body acupuncture on obesity: anthropometric parameters, lipid profile, and inflammatory and immunologic markers. ScientificWorldJournal. 2012;2012:603539.

Zhi-Qi Zhao, PhD: Professor of Institute of Neurobiology, Fudan University, China.

Zhao, ZQ.  Neural mechanism underlying acupuncture analgesia. Prog Neurobiol. 2008 Aug;85(4):355-75.

Functional Magnetic Resonance Imaging (fMRI) and Positron emission tomography (PET) Studies

Harris RE, Zubieta JK, Scott DJ, Napadow V, Gracely RH, Clauw DJ. Traditional Chinese
acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid
receptors (MORs). Neuroimage. 2009;47(3):1077-1085.

Acupuncture as a component of East-Asian medical systems has been used to treat pain for over two millennia however the cellular and molecular constituents of this therapy remain largely unknown. Prevailing theories, arising largely from studies in animals, suggest that endogenous opioids and their associated receptors are involved in this treatment (He et al., 1985Pert et al., 1981Ho and Wen, 1989;Pomeranz and Chiu, 1976Chen et al., 1996). Most studies have focused on the opioid neurotransmitters (Stux and Hammerschlag R, 2001), where enhanced release seems to accompany needle insertion, however less attention has been paid to the opioid receptors themselves (e.g. the μ, κ, and δ opioid receptor classes) and their relationship with clinical response.

Recent controversy in the field of acupuncture research was generated when several large scale randomized controlled trials in chronic pain patients failed to show superiority of acupuncture over sham acupuncture methods (Brinkhaus et al., 2006Linde et al., 2005Melchart et al., 2005Harris et al., 2005). This has lead opponents of acupuncture therapy to suggest that it is no more effective than a placebo intervention. Since placebo administration also induces activation of opioid receptors, specifically the μ-opioid receptor (MOR) class (Benedetti and Amanzio, 1997Zubieta et al., 2005;Amanzio and Benedetti, 1999Levine et al., 1978Pomeranz and Chiu, 1976), acupuncture may indeed operate in part via placebo mechanisms.

Neuroimaging methods allow for the ability to explore the central neurobiological mechanisms of both acupuncture and placebo interventions. Recent functional magnetic resonance imaging (fMRI) studies demonstrate deactivation of limbic structures including the amygdala, the hippocampus, and the perigenual cingulate via a mechanism that is distinct from pain and sham stimulation (Hui et al., 2000;Hui et al., 2005Napadow et al., 2007). Thus while traditional acupuncture and sham acupuncture may have equivalent analgesic effects they may differ significantly in their underlying neurobiological response.

Here we directly explore the involvement of the endogenous opioid system during acupuncture treatment of chronic pain patients diagnosed with fibromyalgia (FM) (Wolfe et al., 1995). FM is a relatively common chronic pain condition thought to originate from augmented pain processing in the central nervous system (Gracely et al., 2002). We have previously demonstrated that FM patients have reduced central μ-opioid receptor (MOR) binding potential (BP; an in vivo measure of binding availability) using 11C-carfentanil (CFN) positron emission tomography (PET) with the μ-opioid selective radiotracer [11C]carfentanil (Harris et al., 2007). In that study patients with greater clinical pain displayed reduced MOR BP. Here we perform CFN PET on FM patients before and following acupuncture and sham treatment. We reasoned that dynamics in receptor binding could complement previous acupuncture research which has focused largely on the release of endogenous opioids. One study has examined acupuncture effects on central opioid receptor binding, however that study used a non-selective opioid receptor agonist and did not examine effects within a clinical population (Dougherty et al., 2008).

Based on animal data and in vitro measures of MOR binding (Gao et al., 1997), it was hypothesized that long-term acupuncture therapy may result in increased MOR BP, or receptor availability in vivo. Further, we reasoned that these effects would not be observed in the sham treatment group, thus differentiating “placebo” from active treatment conditions. Finally, since regional decreases in MOR BP have been associated with greater clinical pain in FM patients (Harris et al., 2007), increases in BP were expected to be associated with reduced clinical pain.

Differential Short-Term Effects of Acupuncture and Sham Acupuncture on MOR Binding. A) Regions of interest showing increased MOR BP following acupuncture as compared to sham treatment. upper left: left nucleus accumbens (lNAC), upper right: three thalamic regions (THA), lower left and right: left amygdala (lAMY), and temporal pole (ltmpole) respectively. B) Percent changes and S.E.M. in MOR BP (treatment1 – baseline1) for all regions identified. Red circles (TA) and black circles (SA) represent group mean values with standard error bars. Overall acupuncture resulted in increases in MOR BP with sham treatment resulting largely in either no change or small decreases in BP.

We provide the first direct evidence of short- and long-term effects of acupuncture therapy on central MOR binding availability in chronic pain patients. Overall we find that traditional acupuncture therapy evokes an increase in MOR availability over both short and long periods. These changes were absent in sham treated patients where either no change was detected or decreases in MOR BP were observed. Reduction in central MOR BP during SA is consistent with increased endogenous opioid release during placebo administration (Zubieta et al., 2005Scott et al., 2008). For both short- and long-term effects of TA, areas showing increases in BP included a number of brain regions classically implicated in the regulation of pain and stress in humans (Zubieta et al., 2001Zubieta et al., 2003b), such as the amygdala, the dorsal and perigenual anterior cingulate, and the insular cortex. Other regions also shown to be involved in responses to pain and other salient stimuli and where TA induced significant effects on MOR BP included the nucleus accumbens, the caudate, and the putamen (Gear and Levine, 1995Scott et al., 2006). The nucleus accumbens and the dorsal cingulate are both regions that we identified previously as showing reduced binding in FM patients as compared to controls (Harris et al., 2007). Finally, a region of the temporal pole showed increases in binding following TA for both short and long time periods, and displayed a significant negative correlation with changes in clinical pain. This temporal pole region has previously been identified as showing responsiveness to negative mood (Kennedy et al., 2006Zubieta et al., 2003b) as well as acupuncture treatment (Napadow et al., 2005;Hui et al., 2000).

Our findings of widespread increases in regional MOR binding availability are consistent with a previous trial of acupuncture in rodents showing that acupuncture induces an increase in the number of central MOR binding sites following treatment (Gao et al., 1997). For changes that arise following long-term therapy, this could involve increased transcription and translation of MORs and their subsequent insertion into the plasma membrane. Indeed acupuncture treatment has been shown to modulate the levels of transcription factors within the central nervous system (Lao et al., 2004). However this explanation does not address the relatively rapid increases in MOR BP that we observe (i.e. within 45 minutes) following needle insertion. One possible explanation originates from animal and tissue preparations where increases in the plasma membrane expression of all three classes of opioid receptors have been shown occur in neurons following excitation. The sub-cellular localization of μ- (Browning et al., 2004), κ-(Shuster et al., 1999), and Δ- (Bao et al., 2003) opioid receptors all appear to be dynamically regulated by neural activity. Following neuronal excitation, all three classes of receptors have been shown to be trafficked to the plasma membrane within the time frame that we observe our short-term acupuncture effects (i.e. within 45 minutes). This type of regulation of glutamate receptors has been observed during long-term potentiation (LTP) and long-term depression (LTD) where neuronal activity modulates receptor expression at the plasma membrane (Malenka, 2003). Interestingly a recent study by Xing et al. suggests that acupuncture can also induce LTD in the spinal cord in a rat model of chronic pain and this depression is abolished by the opioid receptor antagonist naloxone (Xing et al., 2007). LTD-type modulation of MORs and subsequent changes in synaptic strength could function as a mechanism for acupuncture analgesia given the lasting effects of acupuncture observed here and in other clinical trials (Brinkhaus et al., 2006Linde et al., 2005;Melchart et al., 2005Witt et al., 2005).

Another intriguing result from the present study is that although MOR BP values were differentially altered by TA and SA, reduction in clinical pain was similar between groups. In a clinical trial, when an active treatment does not exhibit superior efficacy to a sham or placebo, the active treatment is assumed to be ineffective and only operating via a placebo effect. However this study suggests that this may be an erroneous conclusion. In this instance, our non-insertion sham procedure evoked a similar reduction in pain as our true acupuncture and we speculate that this occurred via a different mechanism. The analgesic effects of SA could have been due to regional reductions in MOR BP, consistent with activation of this class of receptors during placebo effects (Zubieta et al., 2005), whereas TA evoked an increase in receptor binding availability. This interpretation is entirely consistent with the observed positive correlation between decreases in MOR BP within the dorsolateral prefrontal cortex and decreased pain in the SA group. These reductions in MOR BP may also be operating in TA however these effects may be “masked” by the increases in receptor binding availability noted above.

Finally we explored the relationship between increases in MOR BP following acupuncture and subsequent changes in clinical pain. We found that many of the same regions showing increases in binding following acupuncture therapy were also associated with reductions in clinical pain. Since our previous study found reductions in MOR BP in FM patients (Harris et al., 2007), acupuncture may act to increase or “normalize” MOR binding ability in FM patients to levels that are more representative of pain free controls.

Napadow V, Liu J, Li M, et al. Somatosensory cortical plasticity in carpal tunnel syndrome
treated by acupuncture. Hum Brain Mapp. 2006.

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy of the median nerve characterized by paresthesias and pain in the first through fourth digits. We hypothesize that aberrant afferent input from CTS will lead to maladaptive cortical plasticity, which may be corrected by appropriate therapy. Functional MRI (fMRI) scanning and clinical testing was performed on CTS patients at baseline and after 5 weeks of acupuncture treatment. As a control, healthy adults were also tested 5 weeks apart. During fMRI, sensory stimulation was performed for median nerve innervated digit 2 (D2) and digit 3 (D3), and ulnar nerve innervated digit 5 (D5). Surface-based and region of interest (ROI)-based analyses demonstrated that while the extent of fMRI activity in contralateral Brodmann Area 1 (BA 1) and BA 4 was increased in CTS compared to healthy adults, after acupuncture there was a significant decrease in contralateral BA 1 (P < 0.005) and BA 4 (P < 0.05) activity during D3 sensory stimulation. Healthy adults demonstrated no significant test-retest differences for any digit tested. While D3/D2 separation was contracted or blurred in CTS patients compared to healthy adults, the D2 SI representation shifted laterally after acupuncture treatment, leading to increased D3/D2 separation. Increasing D3/D2 separation correlated with decreasing paresthesias in CTS patients (P < 0.05). As CTS-induced paresthesias constitute diffuse, synchronized, multidigit symptomatology, our results for maladaptive change and correction are consistent with Hebbian plasticity mechanisms. Acupuncture, a somatosensory conditioning stimulus, shows promise in inducing beneficial cortical plasticity manifested by more focused digital representations.

Napadow V, Kettner N, Liu J, et al. Hypothalamus and amygdala response to acupuncture stimuli in carpal tunnel syndrome. (full text) Pain. 2007.

Brain processing of acupuncture stimuli in chronic neuropathic pain patients may underlie its beneficial effects. We used fMRI to evaluate verum and sham acupuncture stimulation at acupoint LI-4 in Carpal Tunnel Syndrome (CTS) patients and healthy controls (HC). CTS patients were retested after 5 weeks of acupuncture therapy. Thus, we investigated both the short-term brain response to acupuncture stimulation, as well as the influence of longer-term acupuncture therapy effects on this short-term response. CTS patients responded to verum acupuncture with greater activation in the hypothalamus and deactivation in the amygdala as compared to HC, controlling for the non-specific effects of sham acupuncture. A similar difference was found between CTS patients at baseline and after acupuncture therapy. For baseline CTS patients responding to verum acupuncture, functional connectivity was found between the hypothalamus and amygdala – the less deactivation in the amygdala, the greater the activation in the hypothalamus, and vice versa. Furthermore, hypothalamic response correlated positively with the degree of maladaptive cortical plasticity in CTS patients (inter-digit separation distance). This is the first evidence suggesting that chronic pain patients respond to acupuncture differently than HC, through a coordinated limbic network including the hypothalamus and amygdala.

Cross-sectional fMRI analysis of CTS patients at baseline and healthy controls (HC). The ANOVA interaction tests: (CTSbase.acup – CTSbase.sham) –(HC.acup – HC.sham). A positive interaction was found in the hypothalamus, while a negative interaction was found in the amygdala. Interaction plots demonstrated that the greatest %-signal change in the interaction was by the subgroup: CTS patients at baseline with verum acupuncture stimulation.

Electroacupuncture Studies

Han JS. Acupuncture and endorphins. Neurosci.Lett. 2004;361(1-3):258-261.

Studies on the mechanisms of action have revealed that endogenous opioid peptides in the central nervous system play an essential role in mediating the analgesic effect of EA. Further studies have shown that different kinds of neuropeptides are released by EA with different frequencies. For example, EA of 2 Hz accelerates the release of enkephalin, beta-endorphin and endomorphin, while that of 100 Hz selectively increases the release of dynorphin. A combination of the two frequencies produces a simultaneous release of all four opioid peptides, resulting in a maximal therapeutic effect. This finding has been verified in clinical studies in patients with various kinds of chronic pain including low back pain and diabetic neuropathic pain.

Li A, Lao L, Wang Y, et al. Electroacupuncture activates corticotrophin-releasing hormone containing neurons in the paraventricular nucleus of the hypothalammus to alleviate edema in a rat model of inflammation. (full text) BMC Complement Altern Med. 2008;8:20.

Clinical trials show that electroacupuncture (EA) has beneficial effects in patients with various inflammatory diseases [1]. Studies demonstrate that EA significantly inhibits complete Freund’s adjuvant (CFA)-induced hind paw inflammation and hyperalgesia in a rat model [2,3]. However, the underlying mechanisms of acupuncture are still not completely understood.

We recently demonstrated that EA significantly increased plasma corticosterone levels in rats with hind paw inflammation compared to sham EA control. Adrenalectomy blocked EA-produced anti-edema, but not EA anti-hyperalgesia. RU486, a prototypical glucocorticoid receptor antagonist, also prevented EA anti-edema. These data suggest that adrenal gland-secreted corticosterone mediates EA anti-edema [2,4].

Previous study suggests that the paraventricular nucleus (PVN) of the hypothalamus is involved in acupuncture analgesia. Electrical stimulation of the PVN significantly increased the pain threshold and enhanced acupuncture analgesia [5]. Pituitary gland involvement in EA has been inconclusive. It was reported that hypophysectomy (HYPOX) attenuated acupuncture analgesia in mice [6] and rats [7,8], and that inhibition of the pituitary function by dexamethasone treatment reduced acupuncture analgesia [9]. These data indicate the involvement of the pituitary gland in EA analgesia. However, it was also reported that HYPOX did not alter EA-induced inhibition of the writhing response in mice [10] and that the pituitary gland was not involved in production of EA analgesia in rats [11]. These discrepancies are likely related to the status of the animals (e.g. length of time after surgery) and to the tests used in the studies. All of these studies were conducted on animals with mechanical or chemical pituitary gland damage and transient noxious stimuli. Corticotropin-releasing factor (CRH) and adrenocorticotropic hormone (ACTH) are secreted by the PVN and pituitary gland, respectively, and drive the secretion of corticosterone from adrenal glands. Whether they are involved in EA-produced anti-edema and anti-hyperalgesia has not been previously investigated using their respective antagonists in an inflammatory pain animal model. Because uninjured models do not mimic the chronic pathological conditions seen clinically, we used a CFA-inflamed rat model to test the hypothesis that EA activates CRH-containing neurons in the PVN and increases plasma ACTH levels to ameliorate inflammation and hyperalgesia.

Effects of EA treatment on plasma ACTH levels (% changes vs baseline, n = 6 per group, mean ± SEM). EA treatment induced no significant changes of plasma ACTH in uninflamed rats. CFA-induced inflammation alone resulted in no significant changes in plasma ACTH levels. EA treatment in inflamed rats significantly increased ACTH levels compared to sham EA. *P < 0.05 compared to sham EA.

….The present study found that EA activates CRH-containing neurons in the PVN. The PVN is a pivotal nucleus that responds to various stimuli including stress [21]. However, as discussed below, the EA procedures used in this study have little stress effect. Thus, the neuron activation in the PVN of EA-treated rats is considered a specific response to EA, not a general stress response. Previous study also demonstrates that EA significantly activates the PVN [22]. Our data further show that EA-activated neurons in the PVN contain CRH, which indicates that EA treatment may induce CRH secretion. The secreted CRH acted on CRH receptors to increase ACTH release, which is supported by the data showing that EA significantly increases plasma ACTH levels in CFA-inflamed rats compared to sham EA. These data are consistent with our recent report that EA increases endogenous corticosterone secretion [4]. The secreted CRH and ACTH activated their respective receptors, leading to the inhibition of edema. This is evidenced by our experiments on CRH and ACTH antagonists. Pretreatment with a CRH antagonists, astressin and an ACTH antagonist, ACTH(11–24), prevented EA anti-edema. Taken together, these results suggest that in pathological conditions EA activates the HPA axis to increase CRH, ACTH, and glucocorticoid secretion and suppress inflammatory responses.

Photomicrographs showing co-localization of CRH and p-NR1 in the PVN. A-C: Sections from EA-treated naive rats were double-labeled with anti-CRH (red) and anti-p-NR1 (green). A: CRH-immunoreactive neurons in the PVN. B: p-NRI-immunoreactive neurons in the PVN. C: Merged graphs of A and B. Small arrows indicate examples of double-labeled CRH/p-NR1 neuron (yellow); Arrowheads point to single-labeled CRH and p-NR1. The insets in A, B and C are higher magnification of the square areas in A, B and C, respectively. D: Sections from untreated naive rats were signle-labeled with anti-p-NR1 and showed no labeling of P-NR1. Scale bars represent 50 μm in A, B, C, and 250 μm in D.

…It is also noticed that ACTH(11–24) did not block EA anti-hyperalgesia, suggesting that endogenous ACTH plays little role in EA anti-hyperalgesia. Previous studies using HYPOX showed that the pituitary gland was involved in acupuncture analgesia [7,8]. The discrepancy between previous studies and ours may be due to the difference in animal models, inflammatory vs. uninflamed animals, since EA affects healthy and pathological conditions differently, as stated above. Another difference is that we used antagonists in our study while the previous studies used HYPOX that took away all pituitary-secreted molecules, including beta-endorphin. Logically, less involvement of CRH and no involvement of ACTH in EA anti-hyperalgesia suggest that EA may produce anti-hyperalgesia by affecting the nervous system. Our recent studies [26] demonstrate that EA activates brainstem nuclei, which are involved in descending inhibitory modulation of spinal transmission of noxious messages, to inhibit the transmission of noxious messages at the spinal cord. Our previous studies demonstrate that spinal mu and delta opioid systems are involved in EA anti-hyperalgesia in the same inflammatory pain rat model [12].

….Conclusion: The present study demonstrates that EA activates CRH-containing neurons to significantly increase plasma ACTH levels and suppress edema through CRH and ACTH receptors in a rat model of inflammation. EA-produced inhibition of edema involves the activation of NMDA receptors in CRH-containing neurons of the paraventricular nucleus.

Li P, Ayannusi O, Reid C, Longhurst JC. Inhibitory effect of electroacupuncture (EA) on the pressor response induced by exercise stress. Clin Auton Res. 2004;14(3):182-188.

We examined the effect of EA on the exercise stress-induced pressor response in healthy adult subjects of both sexes. Each subject was subjected to a bicycle exercise test using a ramp protocol once/week for three or four weeks. Subjects were asked to perform the following tests in random order: 1) a baseline exercise test without EA and 2) exercise after acupuncture at P 5-6, LI 4-L 7 and/or G 37-39 acupoints. Brachial systolic (SBP), diastolic (DBP), and mean blood pressures (MBP), heart rate (HR) and the rate-pressure product (RPP, systolic BP x HR/100) were measured every three min, while a 12 lead ECG was monitored continuously. We observed increases in MBP, SBP, HR and RPP in all 17 subjects during exercise. In 12 of the 17 subjects (71 %), EA for 30 min before exercise, either at Jianshi-Neiguan acupoints (P 5-6) or Hegu-Lique acupoints (LI 4-L 7), led to an increase in maximal workload, and reduced peak SBP, MBP and RPP responses to exercise; EA did not alter DBP or HR responses in these subjects. EA at control acupoints (Guangming-Xuanzhong acupoints, G 37-39) in five subjects did not alter the hemodynamic responses. Seven additional subjects were enrolled to study the effect of EA during a bicycle exercise test using a constant workload. The results were similar, in five of the seven subjects SBP, MBP and RPP after exercise were attenuated significantly by EA at P 5-6. We conclude that EA at specific acupoints improves exercise capacity and reduces the hemodynamic responses in approximately 70% of normal subjects.

Zhang RX, Lao L, Wang X, et al. Electroacupuncture attenuates inflammation in a rat model.  JA – J Altern.C. 2005;11(1):135-142

BACKGROUND:

Acupuncture has traditionally been used in China and is being increasingly applied in Western countries to treat a variety of conditions, including inflammatory disease. However, clinical trials investigating the effectiveness of the anti-inflammatory effects of acupuncture have yielded inconsistent results, and the underlying mechanisms of acupuncture-produced anti-inflammation are unclear.

OBJECTIVE:

To evaluate the effectiveness of electroacupuncture (EA) on inflammation in a rat model.

MATERIALS AND METHODS:

Four experiments were conducted on male Sprague-Dawley rats (n = 8-9 per group). Inflammation was induced by injecting complete Freund’s adjuvant (CFA) subcutaneously into the plantar surface of one hind paw of the rat. Experiment 1: To determine the effect of EA (10 and 100 Hz) versus sham treatment on inflammation. Experiment 2: To investigate the involvement of the adrenal glands on the effect of EA treatment using adrenalectomized (ADX) rats. Experiment 3: To determine the effects of EA on plasma levels of corticosterone. Experiment 4: To determine the effects of EA treatment versus immobilization on such stress indicators as heart rate and blood pressure.

RESULTS:

At 10 Hz EA significantly reduced CFA-induced hind paw edema. The effect was partially blocked in the ADX rats. EA significantly increased plasma levels of corticosterone but produced no noticeable signs of stress.

CONCLUSION:

At 10 Hz but not 100 Hz, EA suppresses inflammation by activating the hypothalamus-pituitary-adrenal axis (HPA) and the nervous system.

Interstitial Connective Tissue/ Fascia/ Extracellular Matrix:

Leading Researcher:

Helene Langevin, MD: University of Vermont College of Medicine, Professor, Dept of Neurosciences

From The Scientist: The Science of Acupuncture: May 1, 2013 by Helene Langevin: WHEN CONNECTIVE TISSUE STRETCHES Various types of connective tissue join organ and muscle groups throughout the body. Our research showed that when connective tissue is stretched for at least 30 minutes, either by physical extension1 or by mechanical stimulation with an acupuncture needle2, the fibroblast cells that help produce and maintain the connective-tissue matrix become enlarged and flattened. A current cellular model that could explain this change in shape predicts that focal-adhesion complexes on the surface of the fibroblasts detect the stretching, and initiate a signaling pathway mediated by the protein Rho3. In response, the cell releases ATP into extracellular space. ATP participates in the change in cell shape, and also may be converted into breakdown products with analgesic effects4. In addition, the Rho pathway instigates remodeling of the cell’s focal adhesions5, which mediate where and how the cell attaches to the extracellular matrix. Together these changes cause relaxation of connective tissue.

Studies:

Langevin HM, Yandow JA. Relationship of acupuncture points and meridians to connective tissue planes.  (full text) Anat Rec. 2002;269(6):257-265.

Langevin HM, Bouffard NA, Churchill DL, Badger GJ. Connective tissue fibroblast response to acupuncture: dose-dependent effect of bidirectional needle rotation. (full text) J Altern Complement Med. 2007;13(3):355-360.

Langevin HM, Bouffard NA, Badger GJ, Churchill DL, Howe AK. Subcutaneous tissue fibroblast cytoskeletal remodeling induced by acupuncture: Evidence for a mechanotransduction-based mechanism. J Cell Physiol. 2006;207(3):767-774.

Langevin HM, Konofagou EE, Badger GJ, et al. Tissue displacements during acupuncture using ultrasound elastography techniques. Ultrasound Med Biol. 2004;30(9):1173-1183.

Langevin HM, Churchill DL, Wu J, et al. Evidence of connective tissue involvement in acupuncture. (full text) FASEB J. 2002;16(8):872-874.

Langevin HM, Storch KN, Cipolla MJ, White SL, Buttolph TR, Taatjes DJ. Fibroblast spreading induced by connective tissue stretch involves intracellular redistribution of alpha- and beta-actin. Histochem Cell Biol. 2006:1-9.

Endocrinology of Acupuncture:

Leading Researchers

Elisabet Stener-Victorin, RPT, PhD: Associate professor, Senior Scientist, Department of Physiology, Endocrine division, Göteborg University, Sweden

Studies

Johansson J, Feng Y, Shao R, Lönn M, Billig H, Stener-Victorin E. Intense Acupuncture Normalizes Insulin Sensitivity, Increases Muscle GLUT4 Content, and Improves Lipid Profile in a Rat Model of Polycystic Ovary Syndrome. (full text) Am J Physiology: Endocrinology and Metabolism. 2010;299(4):E551-559.

Fig. 3. Expression of GLUT4 in muscle cells in controls, rats with DHT-induced PCOS, and PCOS-EA rats. Although the immunoreactivity of GLUT4 is less intense in DHT-induced PCOS rat muscle cells (B1–B3) than in controls, GLUT4 is localized predominantly around the nucleus of the muscle cells (A1–A3). EA treatment (C1–C3) increases GLUT4 expression in the plasma membrane and in the cytosol of muscle cells. D: muscle GLUT4 immunoreactivity was absent in the adjacent section when the primary antibody was omitted. Staining was repeated in 4 rats/group with similar results. The immunofluorescence findings shown are representative of those in randomly selected sections from multiple animals. E: hematoxylin-eosin staining in control rats illustrates nucleus of muscle cells. All photographs were taken with a ×20 objective; the exact scale is given in the figure.

The mechanism for the beneficial effects of 4–5 wk of low-frequency EA given 3 days/wk is unknown (5152). Most likely, it involves a direct influence on skeletal muscle signaling mechanisms and secondary actions in adipose tissue. Muscle contraction during low-frequency EA may stimulate glucose uptake via an insulin-independent pathway and may be mediated, at least in part, by signaling pathways in skeletal muscle similar to those activated by chronic exercise (16,25). The signaling mechanisms in skeletal muscle after muscle contraction have been studied extensively (59). Few such studies have been conducted on low-frequency EA. In male rats acutely exposed to prednisolone to induce an insulin-resistant state, low-frequency EA for 60 min during anesthesia restored protein expression of insulin receptor substrate-1 and GLUT4 in skeletal muscle (45). The mechanism by which low-frequency EA improves insulin sensitivity in rats with DHT-induced PCOS remains to be elucidated. Furthermore, it is not known whether low-frequency EA can restore normal insulin sensitivity, as exercise does, when EA is given more frequently in rats with DHT-induced PCOS.

In this study, we tested the hypothesis that low-frequency EA, given 5 days/wk for 4–5 wk at an intensity high enough to evoke muscle twitches, would normalize insulin sensitivity by restoring signaling mechanisms in skeletal muscle and improve the lipid profile of DHT-induced PCOS rats. We measured whole body insulin sensitivity by euglycemic hyperinsulinemic clamp test, body composition by dual-emission X-ray absorptiometry (DEXA), the lipid profile by ELISA, and skeletal muscle protein expression and activation of GLUT4, Akt, and AS160 by Western blot and GLUT4 location by immunofluorescence staining.

This study demonstrates that intensive low-frequency EA, given 5 days/wk for 4–5 wk, restores normal insulin sensitivity, as measured by euglycemic hyperinsulinemic clamp, in rats with DHT-induced PCOS. EA also increased expression of total GLUT4 in different compartments of soleus muscle cells and partly improved the lipid profile in PCOS rats, which may explain, at least in part, the improved insulin sensitivity. Since EA also improves ovarian morphology and cyclicity (235152), these findings suggest that EA interrupts the vicious cycle of androgen excess, insulin resistance, and ovarian dysfunction in PCOS.

Stener-Victorin E, Jedel E, Jansson PO, Bergman-Sverrisdottir Y. Low-frequency Electro-Acupuncture and Physical Exercise Decrease High Muscle Sympathetic Nerve Activity in Polycystic Ovary Syndrome. Am J Physiol Regul Integr Comp Physiol 2009;297(2):R387-95.

Mannerås L, Cajander S, Lönn M, Stener-Victorin E. Acupuncture and Exercise Restore Adipose Tissue Expression of Sympathetic Markers and Improve Ovarian Morphology in Rats with Dihydrotestosterone-Induced PCOS. Am J Physiol Regul Integr Comp Physiol. 2009; 296:1124-1131.

Sham/ Placebo Control/ Study Design Debate

Hugh MacPherson, Richard Nahin, Charlotte Paterson, Claire M. Cassidy, George T. Lewith, Richard Hammerschlag. Developments in Acupuncture Research: Big-Picture Perspectives from the Leading Edge. The Journal of Alternative and Complementary Medicine. Sep 2008, Vol. 14, No. 7: 883-887

Hammerschlag R, Zwickey H. Evidence-based complementary and alternative medicine: back to basics. J Altern Complement Med. May 2006;12(4):349-350.

Hélène M. Langevin, Richard Hammerschlag, Lixing Lao, Vitaly Napadow, Rosa N. Schnyer, Karen J. Sherman. Controversies In Acupuncture Research: Selection of Controls and Outcome Measures In Acupuncture Clinical Trials. (pdf) The Journal of Alternative and Complementary Medicine. Dec 2006, Vol. 12, No. 10: 943-953
Lewith G, White P, Kaptchuk T. Developing a research strategy for acupuncture. Clin J Pain. 2006;22:632–638
Ahn AC, Kaptchuk TJ.  Advancing acupuncture research.  Altern Ther Health Med. 2005 May-Jun;11(3):40-5.

Comments

  1. Everyone seems to be trying to dress a pig up in lambs clothing, why not take it at face value? Qi is an energetic resource and it can be manipulated and when it is maniplated all sorts of outcomes are witnessed. They, the outcomes, are prima facia evidence for the existence of qi.

  2. Hello Andy, thank you for the comment. It seems that many acupuncturists would rather let acupuncture and TEAM in general ‘speak for itself.’ But what does this mean, really?

    TEAM practitioners have been recording their case studies for millennia, using their own research techniques to investigate the details of Qi flow in the body, how it is manipulated and to what end. The tools that those researchers had at their disposal were their highly developed senses and powers of observation. Based on their meticulous investigation of complex processes, they created an incredibly sophisticated diagnostic and treatment system. This system identifies an organizing principle of the body that can be termed ‘Qi.’ Now, Western students can learn about Qi and its presence in the body; we can learn to manipulate it somehow; we can be satisfied with our clinical results based on this process. To you and many other acupuncturists, this may seem to allow the medicine to ‘speak for itself.’ But this system exists in the form we know it only because those original practitioners spent a great deal of time and effort investigating and challenging their own ideas of anatomy and physiology, natural principles such as Qi, internal mechanisms and pathways of action of the body.

    However, modern researchers have access to a whole new set of ways to measure and observe the bodily processes, and many researchers believe there is great merit in learning more about the effects of acupuncture on these additional measurable bodily processes. We also learn more about the human body in general as we investigate these questions, so it’s really a win-win situation for both acupuncturists and those endrocrinologists/ neurologists/ research scientists that collaborate in many of these studies.

    Also, I believe that you may have meant a term other than “prima facie.” In this case it does seem that you meant “res ipsa loquitur.”
    From wikipedia:
    “Prima facie is often confused with res ipsa loquitur (literally, “the thing speaks for itself”), the common law doctrine that when the facts make it self-evident that negligence or other responsibility lies with a party, it is not necessary to provide extraneous details, since any reasonable person would immediately find the facts of the case.
    The difference between the two is that prima facie is a term meaning there is enough evidence for there to be a case to answer. Res ipsa loquitur means that because the facts are so obvious, a party need explain no more. For example: “There is a prima facie case that the defendant is liable. They controlled the pump. The pump was left on and flooded the plaintiff’s house. The plaintiff was away and had left the house in the control of the defendant. Res ipsa loquitur.””

    You are implying that we don’t need to add any descriptive details to the mechanism of Qi flow or Qi stimulation in the body, simply because we can see that ‘something happens’ during an acupuncture treatment. Nevermind the idea that Qi itself is such a large concept that it becomes nearly meaningless when applied to the body in such general terms as you have used. What is Qi? How do you know if it is being manipulated? What is the evidence or outcome of Qi being manipulated rather than some other substance being manipulated? These are questions that acupuncturists have been asking for many years, but now we have other ways to measure these responses.

    We are actually working to build a baseline of proof or evidence (on which one might base a ‘prima facie’ argument), because the burden of proof in our Western culture does land squarely in the medical practitioners’ laps. If we practice a therapy that is merely *believed* to be effective, rather than *proved* to be effective, then we are not actually practicing medicine and can be swept under the placebo rug. This is science, not law- we can’t debate our way into showing others the efficacy of acupuncture. And we also can’t wait until each and every person has tried acupuncture to experience its ‘self-evident’ effects. This is why only roughly 6% of the population (at a high estimate) have ever received acupuncture- it’s too difficult to convince people to just try a completely unknown therapy with very little scientific evidence, in our current cultural climate.

    As this website grows, we will add a forum for discussions such as your comment might provoke. We are also adding more content relating to comparative effectiveness research and clinical outcomes/ case studies, which may elucidate ideas that are more immediately applicable to clinical settings. I hope you check back in!

    Best,
    Beth

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