Background & Aims
Neuropathic pain is often accompanied by mechanical hyperalgesia. Primary hyperalgesia is the exacerbation of pain at the injury site, whereas secondary is enhanced pain beyond that site. Secondary hyperalgesia is associated with central sensitization, enhanced central nervous system nociceptive signal processing. Mechanisms underlying mechanical pain perception and secondary hyperalgesia are not fully understood. The capsaicin-heat pain (C-HP) model can induce secondary mechanical hyperalgesia. Event-related fMRI evaluated 1) brain substrates underlying the perception of pain to punctate mechanical stimuli to the leg, and 2) how they change following central sensitization. We hypothesize that regions involved in the brain mechanisms of punctate mechanical pain will exhibit altered BOLD responses to acute stimulation. By identifying brain regions associated with painful mechanical stimuli, we can develop brain-based therapeutic treatments that mitigate neuropathic pain.
Methods
47 volunteers (25F, 27±5 years old) underwent event-related fMRI and experienced a series of 27 weighted pinprick stimuli, consisting of nine 1s probings of 3 forces in millinewtons: 128 mN, 256 mN, 512 mN. In a separate analysis, 31 volunteers (18F, 28±6 years old) underwent fMRI and experienced the same protocol of 27 weighted pinprick stimuli before and after C-HP induction. The probe sequence for fMRI scans was counterbalanced, and identical for all subjects. Subjects rated pain intensity using a numerical rating scale from 0-100, with 0 defined as no pain and 100 defined as worst possible pain, for each pinprick force after each fMRI session. Functional image datasets were analyzed with FMRIB’s Software Library (FSL). Exploratory global analysis was carried out using FSL fMRI expert analysis tool (FEAT). The mechanical pain analysis used a cluster Z threshold of 4, the hyperalgesia analysis used a cluster Z threshold of 2.3, and both analyses used a cluster P threshold of 0.05.
Results
For mechanical pain analysis, a one-way repeated measures ANOVA of subject pain ratings in response to painful mechanical stimuli detected a significant main effect of stimulus intensity, showing that we were able to elicit different levels of pain (F=26.362, p<0.001). Significant activation in bilateral S2 (Parietal Operculum Cortex ), bilateral Insular Cortex, right S1 (Postcentral Gyrus), bilateral Cingulate Gyrus, and bilateral Thalamus. For hyperalgesia analysis, a two-way repeated measures ANOVA detected: 1) a significant main effect of condition, indicating that C-HP successfully induced secondary hyperalgesia (F=4.689, p=0.038), and 2) a significant main effect of stimulus intensity, showing that we were able to elicit different levels of pain (F=20.183, p<0.001). fMRI group analysis revealed a significant contrast for after>before C-HP in the right Middle Frontal Gyrus and right Precentral Gyrus.
Conclusions
From our analysis, we have determined two major findings: 1) the representation for mechanical pain colocalized with regions that we associate with acute thermal pain processing, and 2) the development of hyperalgesia was associated with increased activation in the right Middle Frontal Gyrus, consistent with previous models of mechanical hyperalgesia.
References
Meeker TJ, et al. “Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.” NeuroImage, 2022; DOI: 10.1016/j.neuroimage.2022.119278.
Greenspan JD, et al. “Thermosensory intensity and affect throughout the perceptible range” Somatosens Mot Res, 2003; DOI: 10.1080/0899022031000083807.
Meeker TJ, et al. “Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Modulatory Network.” Frontiers in Neuroscience, 2019; DOI: 10.3389/fnins.2019.00467.
Seifert F, et al. “Medial prefrontal cortex activity is predictive for hyperalgesia and pharmacological antihyperalgesia”. Journal of Neuroscience, 2009; DOI: 10.1523/JNEUROSCI.4654-08.2009.
Presenting Author
Amanda Dynak
Poster Authors
Topics
- Pain Imaging