Effective connectivity among brain regions associated with slow temporal summation of C-fiber-evoked pain in fibromyalgia patients and healthy controls

Abstract

Temporal summation of "second pain" (TSSP) or "windup" results from the summation of C-fiber-evoked responses of dorsal-horn neurons. This phenomenon is dependent on stimulus frequency (≥.33 Hz) and relevant to central sensitization and chronic pain. Our previous neuroimaging studies characterized brain regions associated with TSSP in normal control (NC) and fibromyalgia (FM) groups. During an fMRI scan, subjects received sensitivity-adjusted repetitive heat pulses at .33 on the right foot. FM subjects required significantly lower stimulus intensities than NC to achieve similar TSSP and no significant group differences in the pain-related brain activity were detected. In our current study, we asked whether the effective connectivity among a set of TSSP-related brain regions identified in our previous work differs amongst FM and NC groups. Structural equation modeling was used to characterize the effective connectivity amongst a priori selected brain areas, including the thalamus, S1, S2, posterior insula, and the anterior midcingulate cortex (aMCC) within the left and right hemispheres. This analysis confirmed our a priori models of effective connectivity among these regions mainly confirmed those hypothesized, yet some unpredicted connections were additionally identified (thalamus to aMCC and aMCC to S1). While the models of effective connectivity were not identical in the FM and NC groups, they were very similar. Additionally, the TSSP related effective connectivity of right and left hemisphere regions was very similar. These results provide evidence for significant overlap of the fundamental brain mechanisms that process sensory and affective information related to TSSP in NC and FM groups.

Perspective: Models of effective connectivity involving pain-related processes were estimated with fMRI data from chronic pain and healthy populations. Models were estimated in both hemispheres, and although similar, fibromyalgia was associated with unique models of pain-related processes. Group differences involved the left hemisphere and S1, S2, and posterior insula.

Figure 1

Effective connectivity model of TSSP-related brain regions. The hypothetical model was based on neuroanatomy, brain imaging, neurological findings, and neurophysiological research.

Figure 2

Fibromyalgia (top) and Normal Control (bottom) left hemisphere models a TSSP-related network. Arrows and text indicate the estimated direction and magnitude of influence respectively. Note: aMCC = Anterior Mid-Cingulate, P-Ins = Posterior Insula, and Thal = Thalamus

Figure 3

Normal Control model of a TSSP-related network in the right hemisphere. Arrows and text indicate the estimated direction and magnitude of influence respectively.

Figure 4

Fibromyalgia model of a TSSP-related network in the right hemisphere. Arrows and text indicate the estimated direction and magnitude of influence respectively.