Age-related differences in pain sensitivity and regional brain activity evoked by noxious pressure
Introduction
The prevalence of chronic pain is known to increase with advancing age, with over 50% of community dwelling older adults estimated to be suffering some form of persistent pain complaint (Gibson, 2003). In addition to a greater likelihood of pain, advancing age is also associated with increasing reports of pain interference (Thomas et al., 2004). However, despite extensive research, current understanding of how ageing impacts on the perception and central nervous system processing of pain is incomplete (Gibson and Farrell, 2004). It is possible to ascribe age-related changes in pain report and impact to increased disease prevalence and severity in older people. However, there is also evidence that aging has effects on pain perception (Gibson and Farrell, 2004, Gibson and Helme, 2001), central pain processing (Gibson et al., 1991), and plasticity of pain responses (Zheng et al., 2000) that are not explained by comorbid disease.
Research into the effect of ageing on experimental pain perception has yielded mixed results, with age-related differences in pain sensitivity varying across different stimulus modalities, durations, and sites of application (Gibson and Farrell, 2004, Helme et al., 2004, Lautenbacher et al., 2005). In general, when pain is induced by heat stimuli, older subjects have demonstrated increased thresholds for just noticeable pain compared with their younger counterparts, while the bulk of studies using noxious electrical stimulation have reported no age-related differences in pain sensitivity (Gibson and Farrell, 2004). In contrast, studies using mechanical pressure (Lautenbacher et al., 2005, Pickering et al., 2002) and ischemic pain stimuli (Edwards and Fillingim, 2001) have reported decreased pain thresholds in older subjects. Further, age-related increases in pain thresholds are most pronounced when stimuli are presented over shorter durations, and applied to more distal regions (Gibson and Farrell, 2004, Helme et al., 2004).
Existing psychophysical research into the effects of ageing on pain perception has for the most part been conducted at the level of pain threshold, and there is consequently very limited evidence by which to evaluate possible age-related differences in pain sensitivity at suprathreshold levels (Gibson and Farrell, 2004). An early study measuring age-related differences in the perceived intensity of noxious thermal stimuli found that compared to young subjects, older subjects tended to rate low-intensity stimuli as less painful, whereas they gave higher pain ratings for stimuli presented at higher intensities (Harkins et al., 1986). Finally, studies examining age differences in pain tolerance have generally reported a tendency for older subjects to withdraw from noxious stimuli at lower intensities compared with their younger counterparts (Gibson and Farrell, 2004).
While previous psychophysical research suggests altered pain perception with advancing age, the specific effects of ageing on supraspinal mechanisms involved in the transmission and processing of noxious input are not known. Atrophy of brain parenchyma in normal ageing has been well documented by both postmortem (Dekaban, 1978, Ho et al., 1980, Miller et al., 1980, Skullerud, 1985, Terry et al., 1987) and in vivo MRI investigations (Allen et al., 2005, Benedetti et al., 2006, Buckner et al., 2004, Greenberg et al., 2006, Jernigan et al., 1991, Salat et al., 2004, Sowell et al., 2003, Walhovd et al., 2005), with widespread and non-uniform grey matter (GM) reduction accelerating beyond the middle of the 6th decade (Raz et al., 2005). In addition, age-related changes in brain histology and metabolism have been reported in individuals with no clinical evidence of neurodegenerative disease (Angelie et al., 2001, Yang et al., 2005). However, the functional consequences of these changes, in particular their contribution toward age-related differences in pain perception and report, are yet to be elucidated.
A wide body of research using functional neuroimaging techniques has identified a network of cortical and subcortical regions involved in the processing of sensory, emotional, and cognitive aspects of the pain experience (Apkarian et al., 2005, Farrell et al., 2005, Peyron et al., 2000). Several of the regions known to be involved in pain processing, including the cingulate, insula, hippocampus, striatum, cerebellum and prefrontal cortex have also been shown to significantly decrease in volume with normal human ageing (Allen et al., 2005, Benedetti et al., 2006, Good et al., 2001, Greenberg et al., 2006, Raz et al., 2003, Raz et al., 2005, Walhovd et al., 2005). Reports of altered pain sensitivity in older people may therefore be explained by age-related central nervous system changes. However, functional neuroimaging of pain research has thus far been primarily conducted with young adults, and the effects of ageing on cerebral responses to noxious input are yet to be determined. A recent functional magnetic resonance imaging (fMRI) study involving seven young and seven older adults reported an age-related decrease in pain-evoked activity in a priori selected ROIs in the primary sensory, insula and supplementary motor cortices (Quiton et al., 2007). While this report provides important insights into the effects of ageing on cortical response to pain, the study's small sample limits the analysis of between-group differences as well as the generalizability of its findings. Since the analysis of between-group differences was confined to specific cortical regions, the effects of ageing on pain system functioning could not determined from this study.
The aim of the present research was therefore to investigate the effects of ageing on supraspinal pain processing by comparing pain sensitivity and pain-related brain activity between healthy young (aged 20–35 years) and older (aged 70+ years) adults. In order to account for possible effects of age-related brain atrophy, any regional between-group differences in brain activity evoked by noxious pressure were assessed with reference to age-related differences in brain volumetry. Older subjects were expected to show increased sensitivity to mechanical pressure compared with younger subjects, requiring lower levels of stimulus intensity in order to elicit a pain report. MRI data were expected to reveal age-related differences in the structure and function of brain regions underlying pain processing. Painful stimulation was expected to evoke significantly greater regional brain activity in younger, compared with older adults. We also expected to find significantly decreased tissue volumes in regions showing age-related decreases in pain-evoked activity.
Section snippets
Subjects
Fifteen young (8 female; mean age = 26 ± 3 years) and 15 older adults (6 female; mean age = 79 ± 4 years) gave informed consent to participate in the study. Young subjects were recruited from staff and students at the University of Melbourne and the general community. Older adults were recruited from a volunteer registry held at the National Aging Research Institute in Parkville, Australia. Prior to inclusion into the study, all participants were screened via telephone interview to exclude conditions
Pain thresholds
Consistent with previous research using mechanical pressure stimuli (Lautenbacher et al., 2005, Pickering et al., 2002), repeated-measures ANOVA revealed a significant effect of age on pain sensitivity [F(1, 28) = 6.52, p < 0.05], with younger subjects requiring a greater level of stimulus to elicit reports of JNP, WP, and MP compared with older subjects (Fig. 2a). However, subjective ratings of the relative unpleasantness of pressure stimuli delivered at each threshold level did not differ between
Discussion
Previous research has demonstrated altered pain sensitivity with advancing age. The present study examined such changes in the context of age-related differences in the structure and function of brain regions involved in pain perception. The psychophysical results of this study support and extend previous research showing decreased thresholds for mechanical pressure pain with ageing (Lautenbacher et al., 2005). Here we have shown for the first time that age-related differences in pain
Conflict of interest
There are no actual or potential conflicts of interest. The study protocol was approved by the Human Research Ethics Committees of the Howard Florey Institute, Melbourne Health, and St. Vincent's Hospital, in accordance with the guidelines outlined by the NH&MRC.
Acknowledgements
We thank the volunteers who participated in the study, Dr. Bruce Barber from the National Ageing Research Institute for assistance with subject recruitment, Dr. Nicolas Trost and Dr. Mark Lorenz from the MR department at St. Vincent's Hospital Melbourne for help with image acquisition, and Eugene Duff for help with analysis of BOLD signal time courses. This study was supported by NH&MRC grants 219291 (SJG) and 400317 (GFE).
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