Augmented Pain Processing in Primary and Secondary Somatosensory Cortex in Fibromyalgia: A Magnetoencephalography Study Using Intra-Epidermal Electrical Stimulation

Abstract

The aim of this study was to investigate augmented pain processing in the cortical somatosensory system in patients with fibromyalgia (FM). Cortical evoked responses were recorded in FM (n = 19) and healthy subjects (n = 21) using magnetoencephalography after noxious intra-epidermal electrical stimulation (IES) of the hand dorsum (pain rating 6 on a numeric rating scale, perceptually-equivalent). In addition, healthy subjects were stimulated using the amplitude corresponding to the average stimulus intensity rated 6 in patients with FM (intensity-equivalent). Quantitative sensory testing was performed on the hand dorsum or thenar muscle (neutral site) and over the trapezius muscle (tender point), using IES (thresholds, ratings, temporal summation of pain, stimulus-response curve) and mechanical stimuli (threshold, ratings). Increased amplitude of cortical responses was found in patients with FM as compared to healthy subjects. These included the contralateral primary (S1) and bilateral secondary somatosensory cortices (S2) in response to intensity-equivalent stimuli and the contralateral S1 and S2 in response to perceptually-equivalent stimuli. The amplitude of the contralateral S2 response in patients with FM was positively correlated with average pain intensity over the last week. Quantitative sensory testing results showed that patients with FM were more sensitive to painful IES as well as to mechanical stimulation, regardless of whether the stimulation site was the hand or the trapezius muscle. Interestingly, the slope of the stimulus-response relationship as well as temporal summation of pain in response to IES was not different between groups. Together, these results suggest that the observed pain augmentation in response to IES in patients with FM could be due to sensitization or disinhibition of the cortical somatosensory system. Since the S2 has been shown to play a role in higher-order functions, further studies are needed to clarify the role of augmented S2 response in clinical characteristics of FM.

Fig 1

Stimulus-response curve (A) and temporal summation of pain (B) in response to standardized intra-epidermal electrical stimulation. Grey squares/bars represent patients with FM (A: n = 19, B: n = 18), white squares/bars represent HC subjects (n = 21). The levels of stimulation (x-axis) were based on individual pain thresholds. PT_25%, PT_100%, PT_175% and PT_250% correspond to 25%, 100%, 175% and 250% of the pain threshold intensity (mA), respectively. Data are expressed as the mean ± SEM.

Fig 2

Spatial distribution of the MEG responses in a representative FM (A) and HC subjects (B). The head is viewed from the top. The trace of each gradiometer response pair represents the magnetic field derivation along the latitude (upper) and longitude (lower). The inserts on the right indicate the enlarged responses recorded from the contralateral S1 (a), contralateral S2 (b) and ipsilateral S2 (c) regions. The black lines represent the cortical response to the NRS 6 (FM) and perceptually-equivalent (HC) conditions. The grey line represents the cortical response to the intensity-equivalent condition (HC only). The vertical dotted lines indicate the stimulus onset.

Fig 3

Group mean source locations (A) and source waveforms (B). (A) The group mean source locations for the NRS6 condition (FM) in blue and for the perceptually-equivalent condition (HC-PE) in cyan superimposed on a standard brain. (B) The group mean source waveform as a function of time. The NRS6 condition (FM) in blue, HC-PE in cyan and the intensity-equivalent condition (HC-IE) in gray. The vertical line indicates the stimulus onset.

Fig 4. The amplitudes of the cS1, cS2 and iS2 in patients with FM and HC subjects.

Repeated measures ANOVAs and independent t-tests showed that cortical responses in response to intra-epidermal electrical stimulation of the hand were higher in patients with FM as compared to both perceptually-equivalent (HC-PE) and intensity-equivalent (HC-IE) conditions in HC subjects. Data are expressed as the mean ± SEM. *p < 0.05, **p < 0.01.

Fig 5. Relationship between the dipole amplitude in the cS2 and clinical pain intensity (VAS, mm).