Greater Somatosensory Afference With Acupuncture Increases Primary Somatosensory Connectivity and Alleviates Fibromyalgia Pain via Insular γ-Aminobutyric Acid: A Randomized Neuroimaging Trial

Abstract

Objective: Acupuncture is a complex multicomponent treatment that has shown promise in the treatment of fibromyalgia (FM). However, clinical trials have shown mixed results, possibly due to heterogeneous methodology and lack of understanding of the underlying mechanism of action. The present study was undertaken to understand the specific contribution of somatosensory afference to improvements in clinical pain, and the specific brain circuits involved.

Methods: Seventy-six patients with FM were randomized to receive either electroacupuncture (EA), with somatosensory afference, or mock laser acupuncture (ML), with no somatosensory afference, twice a week over 8 treatments. Patients with FM in each treatment group were assessed for pain severity levels, measured using Brief Pain Inventory (BPI) scores, and for levels of functional brain network connectivity, assessed using resting state functional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy in the right anterior insula, before and after treatment.

Results: Fibromyalgia patients who received EA therapy experienced a greater reduction in pain severity, as measured by the BPI, compared to patients who received ML therapy (mean difference in BPI from pre- to posttreatment was -1.14 in the EA group versus -0.46 in the ML group; P for group × time interaction = 0.036). Participants receiving EA treatment, as compared to ML treatment, also exhibited resting functional connectivity between the primary somatosensory cortical representation of the leg (S1_leg ; i.e. primary somatosensory subregion activated by EA) and the anterior insula. Increased S1_leg -anterior insula connectivity was associated with both reduced levels of pain severity as measured by the BPI (r = -0.44, P = 0.01) and increased levels of γ-aminobutyric acid (GABA+) in the anterior insula (r = 0.48, P = 0.046) following EA therapy. Moreover, increased levels of GABA+ in the anterior insula were associated with reduced levels of pain severity as measured by the BPI (r = -0.59, P = 0.01). Finally, post-EA treatment changes in levels of GABA+ in the anterior insula mediated the relationship between changes in S1_leg -anterior insula connectivity and pain severity on the BPI (bootstrap confidence interval -0.533, -0.037).

Conclusion: The somatosensory component of acupuncture modulates primary somatosensory functional connectivity associated with insular neurochemistry to reduce pain severity in FM.

Figure 1.. Study Overview.

(A) Non-crossover randomized controlled neuroimaging trial in FM with acupuncture intervention. Behavioral session, resting state functional MRI (rs-fMRI) and proton magnetic resonance spectroscopy (¹H-MRS) were collected at baseline (Pre-tx) and after therapy (Post-tx). (B) Acupuncture locations for EA and ML. All subjects were blindfolded and in supine position. In EA, LI-4 was administered to the dorsal surface of the right hand, and LI-11 was administered to the crease of the right elbow. Bolt symbols indicate where needles received current through the EA device. For ML, a deactivated laser was hovered over the same acupuncture points as in EA for the same duration of time. Abbreviations: Du=Governor meridian, LI=Large Intestine, ST=Stomach, SP=Spleen, GB=Gall Bladder, LV=Liver.

Figure 2.. BPI Severity and MASS Index response to therapy.

(A) EA demonstrated significantly greater post-therapy reduction in BPI Severity compared to ML (Group × Time interaction, p=0.036). (B) Patients receiving EA reported significantly higher somatosensory afference (MASS Index) compared to those receiving ML (Main effect of Group (p<0.001)). Error Bars in both plots indicate Standard Error of the Mean (SEM).

Figure 3.. S1_leg connectivity response to therapy.

(A) In EA, S1_leg connectivity to aINS, pINS, and non-leg S1 increased with treatment. In ML, S1_leg connectivity to a/mINS decreased with treatment. The EA>ML contrast showed that magnitude of S1_leg connectivity increase was higher in EA compared to ML. (B) Within EA, as S1_leg-aINS and S1_leg-pINS connectivity increased, BPI severity decreased post-therapy. Values have been adjusted for age.

Figure 4.. aINS GABA response to EA therapy.

(A) Average of ¹H-MRS voxel in the right aINS across all subjects transformed to MNI space, and corresponding mean and SD of the MEGA-PRESS spectra. (B) Intersection of voxels encompassing both the aINS GABA voxel and the aINS cluster from S1_leg connectivity map. (C) Greater increase in S1_leg-aINS connectivity was associated with greater increase in aINS GABA+(i.u.) concentration post-therapy. (D) Greater increase in aINS GABA+(i.u.) was associated with greater reduction in post-therapy clinical pain in FM. Values have been adjusted for age.

Figure 5.. Mediation analysis and proposed mechanistic model.

(A) Increase in aINS GABA+(i.u.) mediates the relationship between increased S1_leg-aINS connectivity and decreased BPI severity post-therapy. (B) The longitudinally informed mechanistic model proposes that somatosensory afference increases communication between S1_leg and the aINS, producing an effect of increased GABAergic inhibition in the aINS, leading to reduced clinical pain in FM.