Even in a pandemic, bait-and-switch acupuncture studies still get published in Nature

Before the COVID-19 pandemic hit in early 2020, an unfortunately all-too-common topic for me was the proliferation of dubious acupuncture studies from practitioners of what I like to refer to as quackademic medicine. These studies ranged from basic science studies using animal models to clinical trials that were not even really designed to test whether acupuncture works but instead were practically designed to produce a “positive” result, even when the result was negative, while still other studies rebrand “electroacupuncture” as “acupuncture.”

Unfortunately, the fascination with acupuncture in quackademic medicine has been so intense over the last three decades that a disturbing number of doctors appear to believe that acupuncture works (or is at least “worth a shot”). Nearly all of them are unaware of how the history of this “ancient Chinese” treatment (which was, in reality, merely the Asian version of European bloodletting) was retconned by Mao Zedong, producing a narrative that this “ancient treatment” demonstrates a near-miraculous efficacy for, well, just about everything. Never mind that the filiform needles associated with modern acupuncture didn’t exist until around 1930, when a Chinese pediatrician named Cheng Dan’an proposed that needling therapy be resurrected because its actions could be explained through neurology and replaced the previously-used coarse lancet-like needles with the fine needles in use today. Unfortunately, belief in acupuncture has gotten to the point where not only is the director of the National Center for Complementary and Integrative Health (NCCIH) a “true believer” in acupuncture, but other health regulatory authorities, including in the VA hospital system, in their desperation over the opioid epidemic, have embraced it and other quackery as “nonpharmacological treatments for pain” even though it is no more than a theatrical placebo. You can even find credulous discussions of acupuncture in The New England Journal of Medicine and at the American Society of Clinical Oncology.

Last week, I was reminded that even a global pandemic can’t stop dubious acupuncture studies from being published. However, even I was surprised at where the study that I chose as the topic of this week’s post was published: Nature. As most of you know, Nature is considered one of the premier general science journals in the world, publishing papers on everything from medicine, to biology, to geology, to astronomy, to just about every science under the sun. Unfortunately, as I’ve documented in the past, Nature has also demonstrated enough credulity about acupuncture and traditional Chinese medicine to have published a large advertising edition promoting them in 2011 and then, in 2015, a full-throated defense of acupuncture and related quackery.

This time around, my Google alerts (and some readers) picked up a news item and a podcast hawking a study in Nature. The titles were quite—shall we say?—promotional, with the podcast being titled “How electric acupuncture zaps inflammation in mice” and the news article “Electroacupuncture activates neurons to switch off inflammation“. The article itself, from investigators at the Dana-Farber Cancer Institute and from two institutions in China that included the Institute of Acupuncture and Moxibustion, Department of Integrative Medicine and Neurobiology, and Institutes of Brain Science at Fudan University in Shanghai, as well as the Meridians Research Center, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences in Beijing, is the less promotional but still misleading “A neuroanatomical basis for electroacupuncture to drive the vagal–adrenal axis“.

The first thing I noticed, as I have for so many other papers like this, was that this is not an acupuncture paper at all! After all, electricity, its properties, and how to generate and use it were not known to the Chinese “millennia ago”, nor did the technology exist to produce the fine filiform needles currently used in acupuncture. Moreover, acupuncture “meridians,” the lines along the body through which the mysterious life force (a.k.a., “qi”) supposedly flows, the blockage of which sticking needles into them supposedly corrects, were never based on known human anatomic structures, much less those of mice, which were used in the study by Liu et al. I’ve characterized this sort of thing as a “bait and switch” going back many years. Basically, therapy is described as acupuncture (the “bait”) but is in reality nothing more than transcutaneous electrical nerve stimulation (TENS) clumsily grafted onto acupuncture (the “switch”) because acupuncture itself doesn’t work.

One might not-unreasonably expect that electrical stimulation of certain nerves could produce physiological effects. That’s a no-brainer that has nothing to do with whether acupuncture works or not. For instance, anyone who’s ever undergone a nerve conduction study, as I once did a couple of decades ago when I had the misfortune to develop carpal tunnel syndrome, knows this. (It’s a study that could easily be used as torture, let me tell you.) The very basis of nerve conduction is electrochemical, and it can be influenced by electrical currents. That doesn’t make it acupuncture just because you hook electrodes up to acupuncture needles stuck into “acupoints”. Worse, the insistence of using acupuncture points, instead of nerves that might actually have physiological relevance, only muddies the waters, making it less likely that an actual, useful therapy might be derived from the mix of electricity and the vitalism of traditional Chinese medicine that is “electroacupuncture”.

Basically, “electroacupuncture” is nothing more than a “rebranding” of acupuncture (which doesn’t work) that disguises it using something that might work (electrical nerve stimulation), labeling that something that might work as somehow being acupuncture too. After all, the Chinese people of hundreds (or thousands) of years ago who supposedly invented acupuncture did not have knowledge of electricity, nor did they have the technology to construct batteries or generators to run electricity through anything. Reviewers should not let authors of manuscripts submitted to journals get away with calling electroacupuncture “acupuncture,” because it’s not. The editors of Nature should know that, but apparently do not.

Another thing about this article that really disturbed me. Let’s take a look at the abstract and then compare it to actual experimental models used to see. First, here’s the abstract:

Somatosensory autonomic reflexes allow electroacupuncture stimulation (ES) to modulate body physiology at distant sites^1,2,3,4,5,6 (for example, suppressing severe systemic inflammation^6,7,8,9). Since the 1970s, an emerging organizational rule about these reflexes has been the presence of body-region specificity^1,2,3,4,5,6. For example, ES at the hindlimb ST36 acupoint but not the abdominal ST25 acupoint can drive the vagal–adrenal anti-inflammatory axis in mice^10,11. The neuroanatomical basis of this somatotopic organization is, however, unknown. Here we show that PROKR2^Cre-marked sensory neurons, which innervate the deep hindlimb fascia (for example, the periosteum) but not abdominal fascia (for example, the peritoneum), are crucial for driving the vagal–adrenal axis. Low-intensity ES at the ST36 site in mice with ablated PROKR2^Cre-marked sensory neurons failed to activate hindbrain vagal efferent neurons or to drive catecholamine release from adrenal glands. As a result, ES no longer suppressed systemic inflammation induced by bacterial endotoxins. By contrast, spinal sympathetic reflexes evoked by high-intensity ES at both ST25 and ST36 sites were unaffected. We also show that optogenetic stimulation of PROKR2^Cre-marked nerve terminals through the ST36 site is sufficient to drive the vagal–adrenal axis but not sympathetic reflexes. Furthermore, the distribution patterns of PROKR2^Cre nerve fibres can retrospectively predict body regions at which low-intensity ES will or will not effectively produce anti-inflammatory effects. Our studies provide a neuroanatomical basis for the selectivity and specificity of acupoints in driving specific autonomic pathways.

This sounds pretty benign, doesn’t it? Now let’s look at how inflammation was induced in these mice:

Activation of the vagal–adrenal axis can suppress systemic inflammation induced by lipopolysaccharide (LPS), a bacterial endotoxin^10,11,20. Without LPS treatment, proinflammatory cytokines, including tumour necrosis factor (TNF) and interleukin-6 (IL-6), were barely detected in serum (Extended Data Fig. 6a).

As a news report on this study notes:

Neuronal networks have evolved to control organ functions. A technique called electroacupuncture, in which specific points on the body called acupoints are stimulated electrically, has long been used to activate these networks and thereby modulate the functions of certain organs to treat various disorders. It is a key part of an emerging medical field known as bioelectronic medicine^1,2. However, little is known about the neuronal networks that mediate the effects of electroacupuncture at specific acupoints^1,3. Writing in Nature, Liu et al.⁴ show in mice that a set of neurons expressing the protein Prokr2 are needed for electrical stimulation of a hindlimb acupoint to rein in the unbridled inflammatory responses that characterize lethal sepsis.

That’s right. The model used in the experiments involved using electroacupuncture in a mouse model of the inflammatory effects of sepsis. Basically, the authors tortured mice in the name of rebranding electricity as a form of acupuncture by injecting one of the main mediators of bacterial sepsis, lipopolysaccharide (LPS, a bacterial endotoxin), applied electroacupuncture to the mice at the leg Zusanli (ST36) acupoint, located about 2 cm below the knee in humans. If you’ve been reading SBM for a long time, you have, whether you remember it or not, encountered discussions of studies using this acupoint before, for example, once in a study published in Nature Neuroscience that Steve Novella deconstructed, another in two studies that were misinterpreted and claimed that adenosine was the common mediator of acupuncture effects, and another in which the levels of various cytokines were measured after applying differing voltages of “electroacupuncture” to this acupoint. As former contributor Mark Crislip put it in his own inimitable way about this last study:

So they stuck a needle in the ST36 Zusanli point of mice. Which is in the leg, below the knee. Who knew that mice and humans had the same meridians and acupoints? Then they cranked in some voltage and measured various cytokines and other inflammatory mediators under various conditions to see what happens.

The ever-inimitable Dr. Crislip then wrote:

They did not use a random peripheral site to apply the voltage or another acupuncture point as a control. As best I can tell, the study actually had nothing to do with acupuncture. What they demonstrated was electrical stimulation of peripheral nerves or the vagus nerve had anti-inflammatory effects. The use of the specific acupuncture point was, well, pointless.

This is the kind of study that drives me nuts. You could remove all the references to acupuncture and the results would be just as applicable. I suppose it would then lack the sexiness that acupuncture adds. Without acupuncture as a hook, I wonder if it would have been published in Nature Medicine or get the notice it did.

He’s right, the rebranding sells the study, as none of this has anything to do with the prescientific vitalistic quackery that is acupuncture. It’s somewhat interesting neuroscience, but could easily get lost in a whole lot of other somewhat interesting neuroscience, hence the acupuncture hook.

Basically, the Zusanli acupoint seems to be one of the favorite go-to acupoints on one of the magical meridians that acupuncture believers like to study. In any event, it should never be forgotten that inducing the physiological effects of sepsis is in mice is never something that should be undertaken lightly, and doing it in the name of trying to make acupuncture seem to have a scientific basis is incredibly unethical, in my book. I can see why work like this could be done in China, but where was Dana-Farber’s IACUC to protect the interests of the experimental animals and minimize their suffering, given that the Methods section leads me to believe that most of the animal experiments were done at Dana-Farber? Moreover, even the Nature podcast seems to acknowledge the bait-and-switch, albeit unknowingly, by characterizing electroacupuncture as delivering electrical current to nerves (at around 2:45), which has nothing to do with acupuncture, meridians, or qi. The announcer even says:

Although the evidence supporting conventional acupuncture is controversial, electroacupuncture has been shown in several studies to decrease inflammation in mice, if the mouse body is stimulated in just the right way.

I will admit that the current study is definitely more sophisticated than that study from several years ago to which Mark Crislip applied his inimitable description, but all that sophistication went to support a narrative that seeks to demonstrate that acupuncture works. An example of this more sophisticated approach, the authors produced transgenic mice (mice genetically manipulated to make specific proteins in specific neurons and the nerve tracts associated with them) to test electroacupuncture applied to the Zusanli acupoint:

For this study, the goal was to investigate why ES can drive the recently reported vagal–adrenal axis from the hindlimb Zusanli (ST36) acupoint but not from the abdominal Tianshu (ST25) acupoint, at which ES instead drives spinal sympathetic reflexes^10,11 (Fig. 1a). We postulated that somato–vagal–adrenal reflexes are driven by sensory pathways that innervate tissues unique to the hindlimbs compared to the abdomen, such as joints, bones and skeletal muscles. One candidate pathway includes DRG neurons marked by PROKR2^Cre (in which with Cre-mediated recombination marks neurons with persistent or transient expression of prokineticin receptor 2¹³). These neurons innervate deep limb tissues but not skin epidermis¹³.

So, for some reason, electricity to the hindlimb can stimulate the nerve pathways that lead to stimulation of the vagus nerve, which inhibits the release of inflammatory molecules from the adrenal glans and thereby decrease inflammation, but stimulation of other mouse acupoints doesn’t. To study this, the authors did this with dorsal root ganglia (DRG) neurons (don’t worry, I’ll explain):

To characterize PROKR2^Cre neurons, we generated Prokr2^Adv-tdTomato mice, in which the tdTomato reporter was restricted to DRG neurons defined by the developmental co-expression of PROKR2^Cre (ref. ¹³) and Advillin^Flpo (ref. ¹⁴)

And:

To study the functions of PROKR2^ADV neurons, we generated Prokr2^Adv-DTR mice, in which the expression of the diphtheria toxin (DTX) receptor (DTR) was restricted to PROKR2^ADVDRG neurons (Extended Data Fig. 5a, b). Four weeks after DTX injections, 98.0 ± 0.5% of PROKR2^Cre-marked DRG neurons were ablated (Extended Data Fig. 5c), which led to 44.5 ± 7.0% and 72.4 ± 5.7% reductions in TUBB3⁺ and NEFH⁺ fibre densities, respectively, in the periosteum (Extended Data Fig. 5d). Notably, no ablation was observed in the spinal cord or brain (Extended Data Fig. 5e). We refer to these mice as PROKR2^ADV-Abl.

I’ll sum it up. The authors used the a method known as cre-lox to introduce the gene for the diphtheria toxin specifically in specific neurons using DNA sequences that drive the expression of two genes specifically restricted to the DRG. In doing so, they noticed that DRG neurons expressing this tdTomato reporter had a higher representation at limb levels than at thoracic levels and did not overlap with neurons that innervate skin epidermis (the outermost layer of the skin). Next, they used mice in which the diphtheria toxin receptor introduced into the mouse embryos in order to similarly restrict its being made to these neurons. They then eliminated these neurons and nerve fibers by treating the mice with diphtheria toxin, which only destroys the cells that make the receptor for the toxin, to observe the effect of lack of these fibers on electroacupuncture through the Zusanli acupoint. The authors observed that eliminating these neurons also eliminated the observed inhibitory effects due to electroacupuncture in decreasing inflammation and concluded that these neurons have a “role in activation of the vagal–adrenal axis by low-intensity ES,” the vagal-adrenal axis being a neurologic pathway and ES being electroacupuncture stimulation.

Using this model, the authors reported:

In LPS-treated control littermates, 0.5-mA ES at the ST36 site caused a 50% reduction in TNF and IL-6 induction and a 40% increase in survival rates compared with sham ES, and these effects were abolished in PROKR2^ADV-Abl mice (Fig. 2d–g). We have previously reported¹¹ that 0.5-mA ES of the abdominal ST25 acupoint does not drive vagal or sympathetic reflexes and is unable to suppress systemic inflammation. High-intensity ES of the ST25 site can drive sympathetic reflexes and produce weak (through 1.0-mA ES) or strong (through 3.0-mA ES) anti-inflammatory effects independent of vagal efferents¹¹. These effects were unchanged in PROKR2^ADV-Abl mice (Extended Data Fig. 6b–j). High-intensity (3.0-mA) ES of the hindlimb ST36 acupoint also drove spinal sympathetic reflexes and produced anti-inflammatory effects independent of PROKR2^ADV neurons (Extended Data Fig. 7a, b). Thus, PROKR2^ADVneurons are uniquely required for low-intensity ES to drive the vagal–adrenal anti-inflammatory axis from the hindlimb ST36 acupoint.

Yes, you read that. Stimulation of the Zusanli acupoint led to a 40% increase in survival after systemic inflammation induced with LPS, an effect abolished in the mice in which this neurological pathway had been ablated. In terms of absolute numbers, only 20-40% of the mice in the control groups survived. Again, from my perspective, one might justify an experiment like this for a purpose that isn’t delusional or self-deceptive, such as studying what happens after a certain nerve is stimulated with electricity and determining the mechanism for these effects. While that is sort of what these experiments do, everything is overlaid with the language and pseudoscience of acupuncture, even though what this study shows is nothing more than that there is a nerve pathway in mice that, when stimulated with electricity, can lead to a decrease in systemic inflammation. That’s it.

A diagram showing how the ST36 accupoint is hypothesized to stimulate DRG cells and result in activity of the vagus nerve.

A number of other experiments were performed. One set of experiments showed that stimulation of PROKR2^ADV fibers activates an anti-inflammatory axis controlled by the vagus nerve. Those with some knowledge of neuroscience will recognize that the vagus nerve is important in the parasympathetic nervous system, as opposed to the sympathetic nervous system. In general, stimulation of the sympathetic nervous system results in the “fight-or-flight” reflex and tends to be pro-inflammatory, while the parasympathetic nervous system counters that stimulation and tends to be anti-inflammatory. This is a simple (but hopefully not simplistic) way of describing the systems that boils it down to its essence for a lay presentation will allow you to understand the importance of the vagus nerve.

In another set of experiments, the authors cut the peroneal nerve (a nerve in the leg that contains fibers that innervate the deep fascia) and showed that doing so eliminated the anti-inflammatory effect that they had observed due to stimulating the Zusanli acupuncture point, while they noted that cutting the lateral cutaneous nerve, which innervates the skin, had no effect. There are a number of other experiments that were done for various controls and to rule out other possibilities, but I won’t go into them here. Let’s for the moment, take the findings at face value, with one exception. This is not acupuncture, contrary to how Nature’s accompanying news article and podcast characterize its findings with passages like:

Liu and colleagues’ findings reveal the cellular route by which ST36 ES activates the vagal–adrenal network. The cell bodies of the sensory neurons that express Prokr2 are located in structures called dorsal root ganglia in the lower spinal cord, and have long processes in the sciatic (hindlimb) nerve that innervate the ST36 acupoint.

And:

The ST36 acupoint is situated at the point at which the sciatic nerve splits into the sural, tibial and peroneal nerves that extend down the calf, and it was not known which of these nerves is most effective for stimulation with acupuncture^7,11. The location of Prokr2-expressing neurons in the deep tissues below ST36 predicts that the anti-inflammatory effects of low-intensity ST36 ES depend on the deep innervations of the common peroneal nerve, rather than on the more-superficial skin innervations of the cutaneous sural nerves. Indeed, the authors confirmed that cutting the peroneal nerve, but not the tibial or sural nerves, blocks the anti-inflammatory effects of ST36 stimulation.

Personally, I like to think of it more like this. Somehow, one point in one acupuncture meridian as described by acupuncturists who use one system (of several) of acupuncture, by coincidence, appears to correspond to a location (on the mouse, at least), where the application of electrical current can stimulate one nerve that produces a signal along a neurologic pathway that leads to stimulation of the vagus nerve and inhibition of the release of pro-inflammatory molecules by the adrenal glands. After decades of searching, some acupuncture believers, having failed to find an effect on much of anything from just acupuncture, figured out that the electrical stimulation of a handful of acupuncture points (which were never based on physiology or any anatomic structure) could lead to physiological effects, which, as a general concept, should not be a surprise at all given that the entire nervous system works through electrochemical signaling and it would be expected that the application of electricity to certain nerves can affect physiology somehow.

In that vein, let me rephrase the concluding paragraph of the Nature news story about this study, to describe what was really found, and it takes just one relatively minor change in verbiage, which I’ll denote by crossing out one word of the original and inserting a very brief bold italicized phrase:

If electroacupuncture targeted electrical stimulation of a nerve can selectively activate specific neuronal networks, it might be feasible to design ES treatments to induce local effects, similar to pacemakers (electronic devices implanted into the chest to control the heartbeat). Thus, it might eventually be possible to use ES to evoke local anti-inflammatory mechanisms in certain parts of the body — such as an arthritic knee or specific sections of the digestive tract in individuals with chronic inflammatory bowel disorders — without suppressing the whole immune system, increasing the risk of infection or leading to side effects elsewhere in the body.

Notice how little I changed the text. The findings of this study, in fact, have even less to do with acupuncture than the adenosine studies that I wrote about a decade ago. Unlike this new study, those studies, at least, didn’t use electroacupuncture—or even electricity of any kind.

Is the neuroscience interesting? Sure. Nature-level interesting? That’s an interesting thought, which brings me back to Mark Crislip’s question that I quoted above and will rephrase for this study: Without acupuncture as a hook to make it “sexy,” I wonder if this study would have been published in as high profile a journal as Nature or get the notice it did.

Personally, I would bet that the answer would have been “no” to both questions. In fact, I’d bet that this study would never have made it to the pages of Nature if it hadn’t so blatantly rebranded targeted electrical stimulation as acupuncture. (Excuse me, “electroacupuncture”.) If the study had been honest and simply reported its observations that the stimulation of the peroneal nerve at a specific point with low level electricity can produce systemic anti-inflammatory effects in mice through the activation of specific nerve fibers in it that can stimulate a nerve pathway that in turn stimulates the vagus nerve to inhibit the adrenal glands from making epinephrine and other catecholamines, it likely would have been accepted for publication in a perfectly respectable mid-level neuroscience journal somewhere, but, then, that wouldn’t have been a Nature paper, now, would it?