The Placebo Hypoalgesic Response Is Reduced in Healthy Older Adults Showing a Decline in Executive Functioning

Katharina M Rischer,1 Angelika M Dierolf,1 Fernand Anton,1 Pedro Montoya,2 Ana M González-Roldán,2 Marian van der Meulen1 1Department of Behavioural and Cognitive Sciences, Institute for Health and Behaviour, University of Luxembourg, Esch-sur-Alzette, Luxembourg; 2Cognitive and Affective Neuroscience and Clinical Psychology, Research Institute of Health Sciences, Balearic Islands Health Research Institute, University of the Balearic Islands, Palma, SpainCorrespondence: Marian van der Meulen, University of Luxembourg, Maison des Sciences Humaines, 11 Porte des Sciences, Esch-sur-Alzette, L-4366, Luxembourg, Email [email protected]: Aging is accompanied by various changes in pain perception and modulation. However, the influence of older age – and associated neurocognitive changes – on placebo hypoalgesia has not been systematically investigated. Findings to date are inconclusive, ranging from a reduced, to a preserved or even an amplified response in older adults. The aim of this study was to examine age-related changes in the placebo hypoalgesic response magnitude, and the potential modulating effect of executive functions, namely working memory, cognitive flexibility and inhibitory control.Methods: Thirty-nine younger (18– 36 years) and 42 healthy older adults (60– 82 years) completed a series of executive functioning tests. Placebo hypoalgesic responding was assessed via a sham transcutaneous electrical nerve stimulation (TENS) intervention while participants received moderately painful electrical stimuli to their arm. An electroencephalogram (EEG) was recorded during the placebo paradigm and pain ratings were collected.Results: Overall, both age groups showed similar robust placebo hypoalgesic effects: pain ratings and pain-related brain potentials were significantly reduced in response to the sham treatment. Interestingly, worse executive functions in older adults (in particular, working memory and cognitive flexibility) were associated with reduced placebo responses. Moreover, executive functions also moderated the overall age group difference in placebo hypoalgesia: when cognitive flexibility and inhibitory control scores were low, older adults showed a smaller placebo response than younger adults.Conclusion: We demonstrated an age-related reduction in placebo hypoalgesia in older adults showing a decline in executive functioning. This is an important finding, considering the fact that placebo effects contribute to positive treatment outcomes. Our results advocate the assessment of executive functions when investigating the influence of aging on placebo effects, as variable aging trajectories of decline may influence overall group comparisons.Plain language summary: As people age, their pain experience and pain coping skills change. This study explores how aging, and related changes in brain function, affect the ability to experience pain relief from a placebo treatment (placebo hypoalgesia). Previous research has been unclear, showing reduced, unchanged, or even increased placebo responses in older adults. We investigated if aging affects the strength of the placebo effect and whether executive functions (like working memory, flexible thinking, ignoring distractions and controlling impulsive reactions) play a role.We studied 39 younger adults (18-36 years) and 42 older adults (60-82 years). They took tests measuring their executive functions and then received a fake electrical nerve stimulation treatment while experiencing moderately painful electrical stimuli on their arm. We recorded their brain activity and pain ratings.Both younger and older adults reported less pain and showed reduced brain responses to pain after the fake treatment, indicating a clear placebo effect in both groups. Older adults with better executive functions, particularly in working memory and cognitive flexibility, had stronger placebo responses. Moreover, when older adults had good cognitive flexibility and inhibitory control, their placebo responses were as large as those of younger adults.In conclusion, when executive functions are intact, normal placebo pain relief can be experienced in older age. This finding is relevant because placebo effects contribute considerably to treatment outcomes. Our results suggest that assessing a potential decline in executive functions is important when studying the impact of aging on pain (coping).Keywords: cognitive pain modulation, aging, executive functions, event-related potentials, prefrontal cortex