The amygdala and Rx of cLBP

Stimulated by Yu et al 2020,[1] and Zhang et al 2020.[2]

The key paper I am highlighting this week comes from the same imaging centre in Boston that gave us Rewiring the brain with acupuncture.[1] It was another paper that I nearly missed, but a subsequent paper in Acupuncture in Medicine led me to take a closer look.

The paper from Acupuncture in Medicine is considerably less sophisticated,[2] and raises more questions than it answers, but it allows us to make some contrasts in terms of methods. In this paper 31 patients with essential hypertension were randomised to receive one of two acupuncture protocols daily for 5 days per week in two consecutive weeks. Resting state fMRI was performed before and after the first session and then again at the end of the treatment course. The group that was intended to receive the proper treatment (Group A) had LR3 and KI3 needled bilaterally with a technique that would have been close to both the first metatarsal artery at LR3 and the posterior tibial artery at KI3. The other group had LR3 and a sham point needled (Group B). The sham point was 2cm medial to the midpoint of the Stomach meridian in the thigh. This would target rectus femoris or the muscle layer beneath it – vastus intermedius. Quite vigorous manual needling was performed 4 times over the 30-minute session in both groups.

…a failure to stratify for gender

The main drawback of this study was a failure to account for gender differences between the groups. We are presented with no baseline data apart from blood pressure (BP), and presumably this gender difference became apparent at peer review and was subsequently included as a limitation in the discussion. The authors report on within group changes in BP, but there is no comment on the 5.5mmHg difference in diastolic BP at baseline, and there were no between group differences. The latter could have been due to a lack of statistical power, but baseline imbalance due to a randomisation failure may have contributed. By randomisation failure here I really mean a failure to stratify for gender, and therefore the associated disparity in risk factors for hypertension between men and women in China.

The key focus of the study was on differences in resting state (rs) fMRI, but given the limitations described above, these have been somewhat over interpreted to my mind.

…several famous names from acupuncture research

Ok, so that paper has only deserved a mention to serve as a contrast to the one by Yu et al.[1] This group includes several famous names from acupuncture research, and it is clear to see from the methods the influence of perhaps the most well-known of those names.

The study involved 79 patients with chronic low back pain (cLBP) who were randomised to four groups. Before you cry out in concern at the potential loss of statistical power from dividing such a relatively small number in 4, it was effectively 2 groups that were subdivided into augmented and limited context manipulation. The acupuncture was a semi standardised manual acupuncture protocol that was applied 6 times over 4 weeks. The sham groups received non-penetrating needling with the Streitberger needle at 12 sham acupuncture points.

The augmented and limited context manipulations were similar to those used in Kapchuk et al,[3] and the clinical outcome was a scale for bothersomeness that was used by Cherkin et al in their famous cocktail stick trial.[4] As well as a clinical outcome, the main focus of the research was fancy imaging to investigate resting state functional connectivity (rsFC) in key areas of the brain, and look for correlations with the clinical outcomes. From prior research the VTA (ventral tegmental area) and the PAG (periaqueductal grey) were identified as key areas. Four additional regions of interest (ROIs) were nominated a priori based on their roles in pain modulation and reward. These were the ACC (anterior cingulate cortex), mPFC (medial prefrontal cortex), insula and amygdala

The change in bothersomeness was greater in the real acupuncture groups, and this just reached statistical significance. There was no difference between the augmented and limited context, indeed the mean change was numerically greater in the limited context groups.

Left amygdala rsFC with VTA
&
Left amygdala rsFC with PAG

The left amygdala was the ROI with rsFC increases with both the VTA and PAG when the real acupuncture group was compared with the sham group. So, the team used multiple regression analysis to examine the correlation between rsFC in these regions with the clinical changes in bothersomeness. They found that the increases in rsFC between the left amygdala and both the VTA and the PAG correlated with decreases in bothersomeness (this analysis was performed with data from all patients). They also found that pre-treatment rsFC between the left amygdala and the PAG correlated with changes in bothersomeness after treatment, so that the lower the rsFC before treatment, the bigger the change in bothersomeness clinically.

Well if you have managed to keep up with all the acronyms and correlations, you will see that we are now starting to build up a picture of functional changes in the brains of real patients that is consistent with our ideas concerning mechanisms of acupuncture from laboratory data built up over the past 50 years. This is quite exciting, and somewhat of a relief to find that what has been determined on the bench still holds true at the bedside.

what has been determined ‘on the bench’ still holds true ‘at the bedside’

I cannot say I am surprised that the augmented versus limited interactions revealed nothing of interest in this patient group, and I think that is one area of inquiry that needs refining for acupuncture. I suspect we need to include the subtle differences in non-verbal interaction between practitioners and their patients, although I am unsure how this can be best achieved.

References

1         Yu S, Ortiz A, Gollub RL, et al. Acupuncture Treatment Modulates the Connectivity of Key Regions of the Descending Pain Modulation and Reward Systems in Patients with Chronic Low Back Pain. J Clin Med 2020;9:1719. doi:10.3390/jcm9061719

2         Zhang J, Lyu T, Yang Y, et al. Acupuncture at LR3 and KI3 shows a control effect on essential hypertension and targeted action on cerebral regions related to blood pressure regulation: a resting state functional magnetic resonance imaging study. Acupunct Med Published Online First: 12 June 2020. doi:10.1177/0964528420920282

3         Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 2008;336:999–1003. doi:10.1136/bmj.39524.439618.25

4         Cherkin DC, Sherman KJ, Avins AL, et al. A Randomized Trial Comparing Acupuncture, Simulated Acupuncture, and Usual Care for Chronic Low Back Pain. Arch Intern Med 2009;169:858. doi:10.1001/archinternmed.2009.65

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Declaration of interests MC