Age-Related Changes in Pain Perception Are Associated With Altered Functional Connectivity During Resting State

Abstract

Aging affects pain experience and brain functioning. However, how aging leads to changes in pain perception and brain functional connectivity has not yet been completely understood. To investigate resting-state and pain perception changes in old and young participants, this study employed region of interest (ROI) to ROI resting-state functional connectivity (rsFC) analysis of imaging data by using regions implicated in sensory and affective dimensions of pain, descending pain modulation, and the default-mode networks (DMNs). Thirty-seven older (66.86 ± 4.04 years; 16 males) and 38 younger healthy participants (20.74 ± 4.15 years; 19 males) underwent 10 min' eyes-closed resting-state scanning. We examined the relationship between rsFC parameters with pressure pain thresholds. Older participants showed higher pain thresholds than younger. Regarding rsFC, older adults displayed increased connectivity of pain-related sensory brain regions in comparison to younger participants: increased rsFC between bilateral primary somatosensory area (SI) and anterior cingulate cortex (ACC), and between SI(L) and secondary somatosensory area (SII)-(R) and dorsolateral prefrontal cortex (PFC). Moreover, decreased connectivity in the older compared to the younger group was found among descending pain modulatory regions: between the amygdala(R) and bilateral insula(R), thalamus(R), ACC, and amygdala(L); between the amygdala(L) and insula(R) and bilateral thalamus; between ACC and bilateral insula, and between periaqueductal gray (PAG) and bilateral thalamus. Regarding the DMN, the posterior parietal cortex and lateral parietal (LP; R) were more strongly connected in the older group than in the younger group. Correlational analyses also showed that SI(L)-SII(R) rsFC was positively associated with pressure pain thresholds in older participants. In conclusion, these findings suggest a compensatory mechanism for the sensory changes that typically accompanies aging. Furthermore, older participants showed reduced functional connectivity between key nodes of the descending pain inhibitory pathway.

Pain modulatory network is influenced by sex and age in a healthy state and during osteoarthritis progression in rats

“…We first assessed sex and age differences in PAG FC with the whole brain at baseline since sex and age have been shown to be key factors affecting brain connectivity in a healthy state (Da Silva et al, 2020; González‐Roldán et al, 2020; Kong et al, 2010). Young male rats had increased PAG FC with entorhinal cortex, mammillary body, parabrachial pigmented nucleus of the ventral tegmental area, and raphe nuclei relative to YF, old male (OM), and old female (OF) rats (Figure 1a).…”

“…In addition, DNIC response is lost in healthy rats of both sexes as they age, and aging is associated with alterations in brain connectivity, including between PAG and ACC (Da Silva et al, 2020). It is likely that differences in descending pain modulatory networks in a healthy state may contribute to the increased risk of developing chronic pain for females and the higher susceptibility to pain modulatory deficits in the elderly population (Fillingim, 2000; González‐Roldán et al, 2020).…”

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

“…In humans, changes in functional connectivity between the mPFC/ACC and PAG are commonly observed in experimental paradigms that produce emotional, attentional, and placebo/nocebo influences on pain as well following the delivery of analgesic drugs and often interpreted as reflecting engagement of the DPMS ( Wager et al, 2004 ; Wiech et al, 2014 ; Wanigasekera et al, 2018 ; Oliva et al, 2021 ). Moreover, changes in the functional connectivity between regions of the mPFC and the PAG are often correlated with changes in pain perception and/or disease progression ( Cifre et al, 2012 ; Hemington and Coulombe, 2015 ; Harper et al, 2018 ; Segerdahl et al, 2018 ; Wanigasekera et al, 2018 ; González-Roldán et al, 2020 ). Here, we provide evidence in rodents that the PrL, a component of the rodent mPFC, can engage the DPMS to affect nociception, and loss in PrL-P neuron function is causally related to the development of the neuropathic pain state in rats.…”

“…However, net loss of inhibitory control has been noted in a wide variety of human chronic pain disorders, and descending inhibitory systems are depleted and non-functional in animal models of persistent pain ( Yarnitsky, 2010 ; Hughes et al, 2013 ; Hughes et al, 2015 ; Staud, 2012 ; Bannister et al, 2015 ). Similarly, trait deficiencies in endogenous inhibitory control and/or its engagement by peripheral injury are thought to impart individual vulnerability to chronic pain ( Edwards, 2005 ; Yarnitsky, 2010 ; Granovsky, 2013 ; Denk et al, 2014 ; González-Roldán et al, 2020 ). What causes this deficit/loss in the function of the DPMS is not well understood but could help identify critical and generalisable mechanisms of chronic pain development that lay the foundation for the development of more effective therapeutic strategies.…”

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

“…However, net loss of inhibitory control has been noted in a wide variety of human chronic pain disorders and descending inhibitory systems are depleted and non-functional in animal models of persistent pain (Yarnitsky, 2010;Hughes et al, 2013Hughes et al, , 2015Staud, 2013;Bannister et al, 2015). Similarly, trait deficiencies in endogenous inhibitory control and/or its engagement by peripheral injury are thought to impart individual vulnerability to chronic pain (Edwards, 2005;Yarnitsky, 2010;Granovsky, 2013;Denk, McMahon and Tracey, 2014;González-Roldán et al, 2020). What causes this deficit / loss in function of the DPMS is not well understood but could help identify critical and generalisable mechanisms of chronic pain development that lay the foundation for the development of more effective therapeutic strategies.…”