Periaqueductal Gray Activation and Pain Responses in Alzheimer’s Disease

Abstract

Background: Pain is underrecognized and undertreated and pain processing is altered in people with Alzheimer’s disease (AD). The periaqueductal gray (PAG) is essential to pain processing and increased pain has been found to scale with increased PAG BOLD activation. The PAG is damaged by AD, however, most studies do not investigate how AD pathology affects pain processing. Purpose: To evaluate pain responses and PAG activation in people with AD compared to cognitively intact older adults. Methods: Psychophysics and fMRI BOLD signals during experimentally delivered heat stimuli were collected during a previous study. In this study, psychophysical data were analyzed with SPSS and the fMRI pain task of the PAG, and other common pain-processing regions, were analyzed with SPM12 from a sample of age- and sex-matched participants (n = 36, 18 AD; 50% female). Results: There were significant main effects of AD status on the temperature necessary to produce pain perception (p < 0.001) and pain unpleasantness (p = 0.039). While not statistically significant, participants with AD rated mild (p = 0.064, d = 0.60) and moderate pain (p = 0.147, d = 0.35) as more unpleasant than controls with meaningful Cohen’s d effect sizes. PAG activation was greater in AD compared to controls during warmth (p = 0.016) and mild pain (p = 0.003), however, no significant differences in activation (p > 0.05) were found for moderate pain or for the other regions tested. Conclusion: This is the first known study to focus on PAG activation during pain in AD. Findings of greater PAG activation in AD indicate that input to the PAG is at least partially retained in this sample, but PAG function may be altered compared to cognitively intact, matched controls. Psychophysical findings indicate that once pain is recognized it is reported as more unpleasant in AD. These combined results, in light of previous findings of increased pain scaling with increased PAG activation, indicate that people with AD may have greater pain unpleasantness than that of cognitively intact older adults and be particularly vulnerable to suffering from pain.