Changes in resting state functional connectivity after repetitive transcranial direct current stimulation applied to motor cortex in fibromyalgia patients

Abstract

Background: Fibromyalgia (FM) is a chronic, centralized pain condition characterized by alterations in the functional, chemical, and structural brain networks responsible for sensory and mood processing. Transcranial direct current stimulation (tDCS) has emerged as a potential treatment for FM. tDCS can alter functional connectivity (FC) in brain regions underneath and distant to the stimulating electrode, although the analgesic mechanisms of repetitive tDCS remain unknown. The aim of this study was to investigate how a clinically relevant schedule of tDCS sessions alters resting state FC and how these changes might relate to clinical pain.

Methods: Resting state functional magnetic resonance imaging data were collected from 12 patients with FM at baseline, after 5 days of sham treatment, and after 5 days of real tDCS with the anode over the left primary motor cortex (M1) and the cathode over the right supraorbital cortex. Seed to whole-brain FC analyses were performed with seed regions placed in bilateral M1, primary somatosensory cortices (S1), ventral lateral (VL) and ventral posterolateral (VPL) thalami, and periaqueductal gray (PAG).

Results: Stronger baseline FC between M1-VL thalamus, S1-anterior insula, and VL thalamus-PAG predicted greater analgesia after sham and real tDCS. Sham treatment (compared with baseline) reduced FC between the VPL thalamus, S1, and the amygdala. Real tDCS (compared with sham treatment) reduced FC between the VL thalamus, medial prefrontal, and supplementary motor cortices. Interestingly, decreased FC between the VL/VPL thalamus and posterior insula, M1, and S1 correlated with reductions in clinical pain after both sham and active treatments.

Conclusions: These results suggest that while there may be a placebo response common to both sham and real tDCS, repetitive M1 tDCS causes distinct changes in FC that last beyond the stimulation period and may produce analgesia by altering thalamic connectivity.

Fig. 1

Stronger FC at baseline predicts analgesia. a Patients with higher L M1 (seed in white) − L VL (anatomical region outlined in black) connectivity at baseline had a greater reduction in clinical pain across sham and real transcranial direct current stimulation (tDCS) periods (displayed at p = 0.005). b Stronger L S1 (seed in white) − L anterior insula FC at baseline predicted a better clinical response. c Connectivity between the L VL thalamus (seed in white) and the PAG at baseline also predicted patients who would respond to sham and real tDCS treatment. Data shown are Fisher-transformed r values. M1 primary motor cortex, VL ventral lateral, S1 primary somatosensory cortex, PAG periaqueductal gray, VAS visual analogue scale, L left, R right, FC functional connectivity

Fig. 2

Sham transcranial direct current stimulation (tDCS) decreases FC compared with baseline. a Decreased connectivity between the left VPL (seed in white) and left S1, left parahippocampal gyrus, and amygdala after sham tDCS compared with baseline. Plots show changes in FC from baseline to after the sham treatment period for each patient with fibromyalgia. b Decreased connectivity between the right VPL (seed in white) and left IPL. c Decreased connectivity between the PAG (seed in white) and precuneus. Data shown are Fisher-transformed r values. VPL ventral posterolateral, S1 primary somatosensory cortex, parahipp parahippocampal gyrus, amyg amygdala, IPL inferior parietal lobule, PAG periaqueductal gray, L left, R right, FC functional connectivity

Fig. 3

Correlations between changes in FC and changes in clinical pain after sham transcranial direct current stimulation (tDCS). a Decreased FC between the left VL thalamus (seed in white) and left posterior insula was correlated with a reduction in clinical pain after sham tDCS. b Decreased FC between the right VPL thalamus (seed in white) and left M1, right M1, and right S1 correlated with reduced clinical pain after sham tDCS. Data shown are Fisher-transformed r values. VL ventral lateral, VPL ventral posterolateral, M1 primary motor cortex, S1 primary somatosensory cortex, VAS visual analogue scale, L left, R right, FC functional connectivity

Fig. 4

Real transcranial direct current stimulation (tDCS) decreases FC compared with sham. a Decreased connectivity between the left VL (seed in white) and SMA and mPFC after real tDCS. b Decreased connectivity between the right VL (seed in white) and SMA and cerebellum after real tDCS. Plots show changes in FC between sham and real tDCS for each patient with fibromyalgia. Data shown are Fisher-transformed r values. OFG orbitofrontal gyrus, VL ventral lateral, SMA supplementary motor area, mPFC medial prefrontal cortex, L left, R right, FC functional connectivity

Fig. 5

Correlation between change in FC and change in clinical pain after real transcranial direct current stimulation (tDCS). Patients with reduced FC between the L VPL thalamus (seed in white) and left S1/M1 and right posterior insula had greater reductions in clinical pain after real tDCS compared with sham (displayed at p = 0.005). Data shown are Fisher-transformed r values. VPL ventral posterolateral, S1 primary somatosensory cortex, M1 primary motor cortex, VAS visual analogue scale, L left, R right, FC functional connectivity

Fig. 6

Summary of results. Stronger corticothalamic FC and FC between regions with high densities of opioid receptors at baseline predicted a better clinical response across the entire study. Changes in FC were observed after sham transcranial direct current stimulation (tDCS), which could be attributed to placebo analgesia or regression to the mean. Real tDCS caused some distinct long-lasting changes in FC (compared with sham) and may have relieved pain via the inhibition of thalamic activity and subsequent decreases in FC, both of which could have been caused by the release of endogenous opioids. M1 primary motor cortex, S1 primary somatosensory cortex, VL ventral lateral, VPL ventral posterolateral, Ant Ins anterior insula, PAG periaqueductal gray, Post Ins posterior insula, Amyg amygdala, Precun precuneus, SMA supplemental motor area, mPFC medial prefrontal cortex, Cer cerebellum, FC functional connectivity