Stimulated by Chen et al 2021,[1] and Courties et al 2021.[2]
EA – electroacupuncture
key to acronyms
IF – impact factor
IBD – inflammatory bowel disease
NGF – nerve growth factor
TrkA – tropomyosin receptor kinase A (high affinity NGF receptor)
TRPV1 – transient receptor potential vanilloid 1 (aka capsaicin receptor)
DRGs – dorsal root ganglia
CAP – cholinergic anti-inflammatory pathway
VNS – vagal nerve stimulation
tVNS – transcutaneous vagal nerve stimulation (vibrotactile and electrical)
TNF – tumour necrosis factor (an inflammatory cytokine)
LPS – lipopolysaccharide (usually derived from Escherichia coli)
IL – interleukin (eg inflammatory cytokines IL–6 and IL1β)
RA – rheumatoid arthritis
SHA – self home acupuncture
This week I’ve been drawn back to one of my favourite techniques – EA to ST36. This links both papers, despite there being no mention of acupuncture in the second.
Chen et al, who are based at the Johns Hopkins in Baltimore, published in the Journal of Inflammation Research (IF 4.79). They used a rat model of inflammatory bowel disease (IBD) to test the effects of EA on abnormal gut motility and sensitivity in the absence of acute inflammation. Having induced the model, they then waited until the inflammation phase had subsided before performing the experiment.
I was drawn in by this paper because the abstract results included the line:
EA at 100Hz was more effective in improving rectal compliance and visceral hypersensitivity.
100Hz was actually 2Hz burst with 10 impulses in each burst
High frequencies rarely come out on top of low (2–5Hz) or intermediate (10–15Hz) frequencies in laboratory research, so I looked more carefully at the precise details. It turns out that what was labelled as 100Hz was actually a burst of 100Hz for 0.1 of a second every half a second. This is effectively 2Hz burst with 10 impulses in each burst. The very same (well if you swap 100Hz for 80Hz) parameters were the basis of the 2Hz setting of the famous Cefar Acus 4 device. It was this device at 2Hz that Lisa Stener-Victorin found had an influence on ovarian blood flow,[3] when another device without a burst output had no effect at 2Hz. The latter device had optimal effects on ovarian blood flow at 10Hz.[4] The Acus 4 on 2Hz delivered 16 impulses per second in two bursts of 8 impulses.
The bottom line is that this choice of frequency seems to have effects in both the low and intermediate range and may be optimal for both pain and autonomic modulation. This is one of the reasons that I adopted a dense dispersed setting of 2/15Hz on the device we now use routinely on our EA training courses.
Having selected the best EA parameters from a set of three alternatives that had all individually demonstrated effects in past experiments, Chen et al compared daily EA for one hour with sham (same set up but no current). The EA was applied via cardiac pacing wires that had been sutured in place at ST36, with a second 5mm below, and tunnelled under the skin up to the back of the neck where they were externalised. This surgery was performed 7 days before the start of the experiment.
After two weeks of daily EA the outcomes were measured. These involved rectal compliance and visceral hypersensitivity, as well as a variety of histological measures on the distal colon including quantitative immunofluorescence staining.
Whilst the acute effect of EA demonstrated an effect on rectal compliance compared with baseline, there was no difference between EA and sham after two weeks of treatment. There was a significant effect on rectal hypersensitivity; however, and the measures suggest that this was entirely reversed. The histological measures show that this improvement was mirrored by reduced mast cell activation, NGF release and expression of its high affinity receptor (TrkA), as well as reduced expression of TRPV1 on sensory nerve endings in the colon and in the corresponding DRGs. Abnormal fibrosis in the wall of the distal colon was not reversed by EA.
The clinical take-home message is that in patients with IBD who have been treated for any acute flares but still suffer from symptoms related to visceral hypersensitivity, a course of EA at ST36 may help to reverse these symptoms. Furthermore, we know that such treatment is likely to have anti-inflammatory effects via the vagus, so it could conceivably reduce the risk of further flares, which brings me on to the second paper.
The second paper comes from the Sorbonne in Paris. It is a review of vagus nerve stimulation in musculoskeletal disease,[2] and was published in the journal Joint Bone Spine (IF 2.86). It gives a concise summary of the cholinergic anti-inflammatory pathway (CAP) and how it has been elaborated over the last 20 or so years. This story started with the discovery that vagal nerve stimulation (VNS) dampened production of tumour necrosis factor (TNF) in a rat model of septic shock,[5] and acupuncture was indicated as a potential method of indirect vagal stimulation in a review 2 years later.[6] I did not see this paper for some years; however, as the acupuncture indication was in a figure and the term was not found by searching the text.
I did not become aware of a potential role of acupuncture until the publication of the effect of EA at ST36 in mouse models of septic shock by a team from Rutgers led by Luis Ulloa in 2014 in Nature Medicine (IF 22.66).[7] In the same year I met with Luis and had some lengthy discussions about the potential role of EA and the parameters of stimulation. He was very keen on the phrase ‘Bioelectric medicine’.
Some months later I received an invitation from Glaxo to join a special advisory group. I declined in order to avoid potential future conflicts of interest, despite being really curious to find out what was under development.
I was a little put out that there was no mention of EA in the review by Courties et al, but then I realised that they only included human trials, and all of these were in patients with rheumatoid arthritis.
Three different interventions were included: one invasive and two non-invasive. The former was the first to be tried and involved implantation of a vagal nerve stimulator in the neck. Subsequently auricular tVNS and then cervical tVNS was tried. All methods appear to show some effects; however, we have to be careful as few studies excluded selection, performance or detection bias, and some studies were funded by industry. On the positive side most of the outcomes used were objective.
Blood was challenged to produce cytokines by addition of LPS
The invasive VNS is perhaps the most convincing so far and was first tested in seven patients being implanted with VNS devices for suppression of epilepsy.[8] Blood was taken before and after anaesthesia for the surgery and then 4 hours post stimulation. This blood was then challenged by addition of LPS (derived from blending E coli) and the production of cytokines (TNF, IL–6, IL–1β) was measured. This demonstrated a significant fall in cytokines following stimulation. The team then went on to implant VNS devices in 18 patients with RA, and at long term (24 months) follow up, 8 of the 17 continuing in the trial were in remission with VNS alone.[9]
Next a vibrotactile device applied to the cymba concha of the external ear proved superior to the same device applied to the calf in healthy subjects, and demonstrated improvements in patients with RA.[10]
A conference abstract from 2020 details 30 RA patients treated with auricular tVNS for 12 weeks.[11] 27 completed the study and of those 7 went into remission and 11 others attained low disease activity.
Cervical tVNS would result in involuntary closure of the glottis
Cervical tVNS involves applying a stimulator with two metallic contacts over the carotid just medial to the sternocleidomastoid muscle. This is said to stimulate the ‘cervical branch’ of the vagus nerve, although I strongly doubt that as it would result in involuntary closure of the glottis, which is rather limiting to one’s breathing! Anyway, this did not stop NICE from allowing its use.[12] I briefly mentioned this is a previous blog about NG59: Too NICE.
I investigated this device previously and the only evidence for the purported vagal stimulation was a single paper on functional imaging of the brainstem that was funded by the manufacturer.[13] The same group had previously performed a similar study on auricular tVNS, which was not funded by industry.[14]
Well, cervical tVNS has been studied in 36 RA patients: 16 with high disease activity and 20 with low disease activity. This open label pilot study looks as though it comes from a reliable group with no industry ties.[15] It demonstrated some effect in patients with high disease activity but not in those with low disease activity.
Finally, we have a paper testing a tiny new invasive stimulator,[16] and published in Lancet Rheumatology (IF none yet), a journal that has only been going 18 months. It is an industry funded study on 14 RA patients and is a great example of how you can spin out a positive message from a trial that essentially shows nothing.
So, where does ST36 EA come in here?
Two patients who were formerly drug resistant went into remission with SHA
I have been using it now for over 5 years for prophylaxis of inflammation in patients with RA and other chronic inflammatory conditions. I teach the patients to apply the treatment themselves twice a week for 20 minutes using 2/15Hz and ideally 1.5 to 3mA at ST36 and Zongping (a point 1 cun below). Unfortunately, I have not kept track of all the patients, but at least two, who were formerly drug resistant went into remission. This simple self-EA technique really needs to be tested in a cohort of RA patients and reading this paper has really motivated me to try to push for this to get done.
References
1 Chen Y, Cheng J, Zhang Y, et al. Electroacupuncture at ST36 Relieves Visceral Hypersensitivity via the NGF/TrkA/TRPV1 Peripheral Afferent Pathway in a Rodent Model of Post-Inflammation Rectal Hypersensitivity. J Inflamm Res 2021;14:325–39. doi:10.2147/JIR.S285146
2 Courties A, Berenbaum F, Sellam J. Vagus nerve stimulation in musculoskeletal diseases. Joint Bone Spine Published Online First: 3 February 2021. doi:10.1016/j.jbspin.2021.105149
3 Stener-Victorin E, Kobayashi R, Watanabe O, et al. Effect of electro-acupuncture stimulation of different frequencies and intensities on ovarian blood flow in anaesthetized rats with steroid-induced polycystic ovaries. Reprod Biol Endocrinol RBE 2004;2:16. doi:10.1186/1477-7827-2-16
4 Stener-Victorin E, Fujisawa S, Kurosawa M. Ovarian blood flow responses to electroacupuncture stimulation depend on estrous cycle and on site and frequency of stimulation in anesthetized rats. J Appl Physiol 2006;101:84–91. doi:10.1152/japplphysiol.01593.2005
5 Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458–62. doi:10.1038/35013070
6 Tracey KJ. The inflammatory reflex. Nature 2002;420:853–9. doi:10.1038/nature01321
7 Torres-Rosas R, Yehia G, Peña G, et al. Dopamine mediates vagal modulation of the immune system by electroacupuncture. Nat Med 2014;20:291–5. doi:10.1038/nm.3479
8 Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A 2016;113:8284–9. doi:10.1073/pnas.1605635113
9 Koopman FA, Musters A, Backer MMJ, et al. Vagus Nerve Stimulation in Patients with Rheumatoid Arthritis: 24 Month Safety and Efficacy. Arthritis Rheumatol 2018;70:abstract number 2536.
10 Addorisio ME, Imperato GH, de Vos AF, et al. Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear. Bioelectron Med 2019;5:4. doi:10.1186/s42234-019-0020-4
11 Marsal S, Corominas H, De Oro JJDA, et al. Non-invasive Vagus Nerve Stimulation Improves Signs and Symptoms of Rheumatoid Arthritis: Results of a Pilot Study. Arthritis Rheumatol 2020;72:abstract 1995.
12 Overview | Transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine | Guidance | NICE. https://www.nice.org.uk/guidance/ipg552 (accessed 2 Mar 2021).
13 Frangos E, Komisaruk BR. Access to Vagal Projections via Cutaneous Electrical Stimulation of the Neck: fMRI Evidence in Healthy Humans. Brain Stimulat 2017;10:19–27. doi:10.1016/j.brs.2016.10.008
14 Frangos E, Ellrich J, Komisaruk BR. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimulat 2015;8:624–36. doi:10.1016/j.brs.2014.11.018
15 Drewes AM, Brock C, Rasmussen SE, et al. Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study. Scand J Rheumatol 2021;50:20–7. doi:10.1080/03009742.2020.1764617
16 Genovese MC, Gaylis NB, Sikes D, et al. Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study. Lancet Rheumatol 2020;2:e527–38. doi:10.1016/S2665-9913(20)30172-7
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