Early last month, I communicated in a blog post a few questions I had about a study in Electro Acupuncture published in PLOS One. It took the authors a while to get to them, but the senior and corresponding author of that study, Professor Kai-Liang Wu, of the Fudan University Shanghai Cancer Center, graciously wrote a detailed reply to my question a week ago. I am going to put his response in this space in blocks. For better comprehension, I shall put my questions in italicized letters followed by his response; the boldface types are for emphasis, mine. My comments are interspersed with the blocks.
We greatly appreciate your helpful comments regarding our manuscript, and our point-by-point responses to each comment are outlined below.
1. Given that classical acupuncture was developed – and acupuncture points mapped out – for humans, how appropriate is the use of the two acupoints on rats in this study? How were their precise locations determined for use, and where is the evidence that those acupoints on the rats are functionally equivalent to the described acupoints in humans?
Response: The location of acupoints on rats/mice is the foundation of experimental research for acupuncture. We located the acupoints on the rats according to a classic rat map, which was drawn at Nanjing Agricultural University in 1991 according to the experience of Chinese veterinarians and experimental studies. We cannot say for certain that the acupoints on the rats are perfectly functionally equivalent to the described acupoints in humans. Although we observed the protective effects of acupuncture after brain irradiation on rats, clinical trials are required to determine if this effect could be reproduced in humans.
In effect, then, the rodent acupuncture points are not “classical”, but were made up in 1991. Although Prof. Wu didn’t provide any reference to the so-called “experimental studies” that were done for this purpose, I am willing to take his word for it. Noteworthy here is the fact that even almost 25 years after the “rat map” was devised, there is no certainty (probably because of no studies, perhaps?) that these acupoints are functional equivalents of those used in humans. How, then, does any author of acupuncture studies in rodent models make any legitimate claim about any putative effect of acupuncture in relation to human disease conditions?
2. Given that electro-acupuncture (EA) as a modality was unknown in traditional Chinese medicine, how appropriate is its use as a substitute for standard acupuncture? Are the actions and effects of standard acupuncture and EA done at the same acupoints different from each other? Is there any evidence to that effect? Was this assessed for the purpose of this study?……I have a few more questions about the specificity of EA.
Response: Electric acupuncture has been widely used in Chinese clinical work. Some researchers have focused on the differences between manual and electric acupuncture (J Altern Complement Med. 2015;21(3):113-28; J Tradit Chin Med. 2014;34(6):754-8), but this was not the purpose of the present study. Different manual manipulations and electrical parameters exert different therapeutic acupuncture effects, which are closely related to the characteristics of the diseases being treated.
We did not observe any effects on the normal rats after electric acupuncture in this study, but some research using electric acupuncture-pretreatment has shown that electric acupuncture may activate STAT3 and MCPIP1 (Brain Res. 2013 Sep 5;1529:154-64; J Neuroinflammation. 2013 May 10;10:63). Unfortunately, we did not detect these molecules in this study.
In other words, then, even at the same acupoint, manual manipulation and electrical stimulation are expected to produce different responses. In the 2014 JTCM paper (referenced by Prof. Wu), which did a literature review to compare the two, the authors write: ““… in acupuncture treatment, the manual manipulations and electrical parameters should be adopted according to syndrome differentiation of TCM.” The pattern of prodigious hand-waving here is clear to see; the burden of observations from two different acupuncture interventions at the same site is facilely transferred to the condition it is supposed to treat. It is like saying: “Here is a bottle of perfumed hair oil. Apply it liberally, but whether it will cure your headache depends on whether you have a brain aneurysm or hydrocephalus.” Which hardly makes any medical sense whatsoever.
This is dealt with in even greater detail in the second reference Professor Wu has indicated (JACM 2015), which is also a review of literature. Without going into too great a detail, let me quote a fundamental problem that the authors have pointed out:
“… two areas of weakness in the acupuncture evidence base. First, models of the mechanisms of action of acupuncture are often based on basic science studies using solely EA or MA without rigorous testing of whether the physiologic effects are similar in both cases. Second, clinical recommendations and individual practitioner decisions for when to use EA or MA are based far more on clinical experience than on clinical research.”
[NOTE: For me, this review assumes even greater importance because of the first author, Helene Langevin, of Harvard. Why? Because in 2002, Langevin and her then-colleague at the University of Vermont, Jason Yandow, claimed to have provided evidence in favor of the so-called “acupuncture meridians”, whose very existence was hitherto in doubt, aligning with physical anatomical structures in the body. I would urge the reader to peruse the masterful deconstruction of the Langevin-Yandow hypothesis by Ben Kavoussi, himself a trained acupuncturist, who referred to the historical texts of Chinese medicine. The two most damning of the facts Ben pointed out were:
- Many of the manuscripts from ancient China – considered definitive guides to acupuncture – were in reality manuals of medical astrology, steeped in myths and imagination.
- The original anatomical localizations in Traditional Chinese Medicine texts followed blood vessels, because the practice was similar to bloodletting. The current map of acupoints that Langevin and Yandow focused on was devised in the 1930s by an early 20th century Chinese physician who moved the acupuncture loci away from the blood vessels.
Regardless, Helene Langevin is something of an authoritative acupuncture celebrity, and her views carry a good deal of weight in this field.]
3. Was there a control where the same amount of electricity was applied to the acupoints without using the acupuncture needles?
Response: We appreciate the excellent suggestion; however, we did not design such a control group in this study. In the future, we will consider adding this type of control. Indeed, some research has shown similar effects between electric acupuncture and transcutaneous electrical nerve stimulation (Int J Clin Exp Med. 2015 Jan 15;8(1):1156-61).
4. Was there a control where the acupuncture needles were placed in acupoints different from the two used and electricity was applied?
Response: In the present study, we only placed the acupuncture needles at the Baihui and Shuigou points. In another study (unpublished), we used the Baihui and Zusanli points, and observed protective effects. However, we did not compare the differences between these two combinations. Thanking you for your suggestion and that we will consider comparing them in the future.
To me, this hearkens back to Langevin et al.‘s recent review and the conclusions they drew (as mentioned above). In the absence of these controls, the specificity of the acupuncture procedures as claimed cannot be established. Transcutaneous electrical nerve stimulation (TENS) is not an acupuncture-related technique at all, despite superficial similarities in appearances with EA; in fact, for their analysis of acupuncture clinical trials, Langevin et al. excluded TENS procedures. We also cannot be sure about the specificity of the acupoints for which efficacy has been claimed. I am rather surprised that the reviewer(s) and the editor, who worked with the authors on this article, did not insist on these basic lines of evidence.
5. In human patients, when the acupuncture needles are inserted, they are often rotated until the patient expresses the sensation of warmth or mild pain/discomfort – which the acupuncturists define as ‘de qi’, taken to be indicative of the correct placement of the needle required for successful treatment. How is this assessed in a rat? The results that the authors have presented appear to show undeniably that following EA, the levels of most variables tested have come down to the levels of naive controls, compared to the irradiated group. I would like to understand if this observed effect is specifically due to acupuncture, due to EA as a modality, or due to non-specific phenomenology associated with transdermal or transcutaneous electrical stimulation.
Response: In the present study, we lifted, thrust, and rotated the needles before electric stimulation. However, it is hard to determine whether the rats experienced “de qi.” This is the main limitation in animal studies of acupuncture. We believe that both manual and electric acupuncture exert their effects by stimulating the nerve (Nat Neurosci. 2010;13(7): 883-8; Nat Med. 2014;20(3):291-5). Therefore, there are no essential differences between the two methods; only the manner in which the nerve is stimulated is different. Currently, it remains unclear which stimulation method is most suitable for treating brain irradiation injuries.
Sincerely, [et cetera]
And yet, in their exhaustive review, Langevin et al. stress an important concept which flies in face of Professor Wu’s protestations of similarity between manual acupuncture and EA.
“… Needling techniques, whether MA or EA, are widely heterogeneous. Manual stimulation techniques may include rotation of the needle in one or both directions and lifting and thrusting of the needle in myriad combinations. These techniques may range from subtle and barely perceptible to vigorous, rapid, and forceful. EA techniques vary by stimulation amplitude, frequency, waveform, and duration. Clinically, EA is often performed after the needle has been manually stimulated sufficiently to obtain de qi, the characteristic needling sensation commonly associated with acupuncture.”
Suffice it to say, the inherent variability of the procedure throws a big question mark on the presumed efficacy of the acupuncture techniques.
In the 2010 Nature Neuroscience article (referenced by Professor Wu), Goldman et al. showed that stimulation of adenosine receptor A1R – either chemically (via an agonist) or via acupuncture at the Zusanli acupoint (located below the knee) – transiently alleviated inflammatory pain in the ipsilateral (on the same side) hindpaw of mice, whereas stimulation of contralateral (on the other side) Zusanli did not. The authors hypothesized that their method of deep tissue stimulation by acupuncture may have been proximal to an ascending nerve track, and the released adenosine reduced the pain by inhibiting the pain-sensing neurons on the same side. It is possible (I suspect) that adenosine’s effect is not strong or sustained enough to affect the contralateral side similarly.
Similar effects of stimulation at the Zusanli point were reported in mouse studies by Torres-Rosas et al. in the other article, 2014 Nature Medicine paper, referenced by Professor Wu. The authors reported the ability to stimulate the vagus nerve via electroacupuncture stimulation, which controlled systemic inflammation due to polymicrobial peritonitis. However, it is difficult to gauge the individual contribution of acupuncture as such, since – as the authors indicated – direct electrical stimulation of the sciatic nerve achieved similar reduction of inflammation.
Both these papers deal with presumed pain-relieving properties of acupuncture modalities observed in small animal models; in contrast, the health benefits claimed by acupuncturists are generally vast and diverse. In general, regardless of the exact mechanisms, for these claims to reach any validity, they would need to be established in human patients via empirical studies, as well as clinical trials. While animal models are not subject to “placebo effect” – therefore, the observed effects are empirically true – the scope of the effects is by design and by necessity much limited in them; mechanisms and pathways in animal models may not always reflect human conditions. Several of these confounding factors are identified in Langevin et al.‘s review; others are pointed out in a 2010 NEJM Clinical Therapeutics feature by Berman, Langevin, and others, who state while explaining observations of sham acupuncture being equally effective as real acupuncture:
“… the specific therapeutic effects of acupuncture, if present, are small, whereas its clinically relevant benefits are mostly attributable to contextual and psychosocial factors, such as patients’ beliefs and expectations, attention from the acupuncturist, and highly focused, spatially directed attention on the part of the patient.”
Professor Wu’s answers, therefore, raise more questions. (I’d probably not re-ask them in the PLOS One comments, though.)