Counterirritation by pain inhibits the responsiveness to aversive loud tones: the role of state anxiety and state fear triggered in the NPU paradigm.

AIM OF THE STUDY: The application of a noxious stimulus reduces the perception and responsiveness to other pain stimuli. This inhibition can be experimentally assessed with a method called 'counterirritation'. The question arises if counterirritation acts also on the perception and responsiveness to aversive but non-nociceptive stimuli (e.g., loud tones). Since aversive stimulation is often associated with state anxiety or state fear, we investigated in addition the modulatory effects of these emotions on counterirritation. MATERIAL AND METHODS: 51 subjects participated in our study. We presented tones with aversive loudness (105 dB), first alone then during counterirritation (immersion of the hand in a hot water bath of 46 °C) to assess inhibition of loudness perception and responsiveness. Influences of state anxiety and state fear on counterirritation were investigated by using the Neutral-Predictable(fear)- Unpredictable(anxiety) Paradigm (NPU), which is based on classical conditioning. Loudness ratings (perception of the aversive tones) and startle reflex (defensive reaction to aversive tones) were assessed. RESULTS: Counterirritation reduced startle reflex amplitudes, but not the loudness ratings. Although state anxiety and state fear were successfully induced, counterirritation remained unaffected. CONCLUSIONS: Our study showed that pain inhibits the responsiveness to aversive stimuli (loud tones). Thus, the postulate that 'pain inhibits pain' might be better changed to 'pain inhibits aversiveness'. Consequently, our findings may also question the assumption of a clear pain specificity in inhibitory action as assumed by theoretical approaches like 'conditioned pain modulation' (CPM). Furthermore, counterirritation appeared one more time resistant to the influence of negative emotions.

Sex differences in facial expressions of pain: results from a combined sample.

ABSTRACT: Facial expressions of pain play an important role in pain diagnostics and social interactions. Given the prominent impact of sex on various aspects of pain, it is not surprising that sex differences have also been explored regarding facial expressions of pain; however, with inconclusive findings. We aim to further investigate sex differences in facial expressions of pain by using a large, combined sample to maximize statistical power. Data from 7 previous studies of our group were merged, combining in total the data of 392 participants (male: 192, female: 200). All participants received phasic heat pain, with intensities being tailored to the individual pain threshold. Pain intensity ratings were assessed, and facial responses were manually analyzed using the Facial Action Coding. To compare facial and subjective responses between sexes, linear mixed-effects models were used, with study ID as a random effect. We found significant sex differences in facial responses, with females showing elevated facial responses to pain, although they received lower physical heat intensities (women had lower pain thresholds). In contrast, pain intensity ratings did not differ between sexes. Additionally, facial and subjective responses to pain were significantly associated across sexes, with females showing slightly stronger associations. Although variations in facial expressions of pain are very large even within each sex, our findings demonstrate that women facially communicate pain more intensively and with a better match to their subjective experience compared with men. This indicates that women might be better in using facial communication of pain in an intensity-discriminative manner.

Is conditioned pain modulation (CPM) affected by negative emotional state?

BACKGROUND: Conditioned pain modulation (CPM) is an experimental paradigm, which describes the inhibition of responses to a noxious or strong-innocuous stimulus, the test stimulus (TS), by the additional application of a second noxious or strong-innocuous stimulus, the conditioning stimulus (CS). As inadequate CPM efficiency has been assumed to be predisposing for clinical pain, the search for moderating factors explaining inter-individual variations in CPM is ongoing. Psychological factors have received credits in this context. However, research concerning associations between CPM and trait factors relating to negative emotions has yielded disappointing results. Yet, the influence of anxious or fearful states on CPM has not attracted much interest despite ample evidence that negative affective states enhance pain. Our study aimed at investigating the effect of fear induction by symbolic threat on CPM. METHODS: Thirty-seven healthy participants completed two experimental blocks: one presenting aversive pictures showing burn wounds (high-threat block) and one presenting neutral pictures (low-threat block). Both blocks contained a CPM paradigm with contact heat as TS and hot water as CS; subjective numerical ratings as well as contact-heat evoked potentials (CHEPs) were assessed. RESULTS: We detected an overall inhibitory CPM effect for CHEPs amplitudes but not for pain ratings. However, we found no evidence for a modulation of CPM by threat despite threat ratings indicating that our manipulation was successful. DISCUSSION: These results suggest that heat/thermal CPM is resistant to this specific type of symbolic threat induction and further research is necessary to examine whether it is resistant to fearful states in general. SIGNIFICANCE: The attempt of modulating heat conditioned pain modulation (CPM) by emotional threat (fear/anxiety state) failed. Thus, heat CPM inhibition again appeared resistant to emotional influences. Pain-related brain potentials proved to be more sensitive for CPM effects than subjective ratings.

Vicarious facilitation of facial responses to pain.

INTRODUCTION: Observing facial expressions of pain has been shown to lead to increased subjective, neural and autonomic pain responses. Surprisingly, these vicarious facilitation effects on its corresponding response channel, namely facial responses to pain have mostly been neglected. We aim to examine whether the prior exposure to facial expressions of pain leads to a facilitation of facial responses to experimental pain; and whether this facilitation is linked to the valence (pain vs. neutral expression) or also linked to specific motor-features of the facial pain expressions (different facial muscle movements). METHOD: Subjective (intensity and unpleasantness ratings) and facial responses (Facial Action Coding System) of 64 participants (34 female) to painful and non-painful heat stimuli were assessed. Before each heat stimulus, video clips of computer-generated facial expressions (three different pain expressions and a neutral expression) were presented. RESULTS: The prior exposure to facial expressions of pain led to increased subjective and facial responses to pain. Further, vicarious pain facilitation of facial responses was significantly correlated with facilitation of unpleasantness ratings. We also found evidence that this vicarious facilitation of facial responses was not only linked to the presentation of pain versus neutral expressions but also to specific motor-features of the pain cue (increase in congruent facial muscle movements). DISCUSSION: Vicarious pain facilitation was found for subjective and facial responses to pain. The results are discussed with reference to the motivational priming hypothesis as well as with reference to motor priming. SIGNIFICANCE: Our study uncovers evidence that facial pain responses are not only influenced by motivational priming (similar to other types of pain responses), but also by motor-priming. These findings shed light on the complexity - ranging from social, affective and motor mechanisms - underling vicarious facilitation of pain.

Facial expressions of pain: the role of the serotonergic system.

RATIONALE: Although interest in the neurobiology of facial communication of pain has increased over the last decades, little is known about which neurotransmitter systems might be involved in regulating facial expressions of pain. OBJECTIVES: We aim to investigate whether the serotonergic system (5-HT), which has been implicated in various aspects of pain processing as well as in behavioral response inhibition, might play a role in facial expressions of pain. Using acute tryptophan depletion (ATD) to manipulate 5-HT function, we examined its effects on facial and subjective pain responses. METHODS: In a double-blind, placebo-controlled within-subject design, 27 participants received either an ATD or a control drink in two separate sessions. Approximately 5-h post-oral consumption, we assessed pain thresholds (heat, pressure) as well as facial and subjective responses to phasic heat pain. Moreover, situational pain catastrophizing and mood were assessed as affective state indicators. RESULTS: ATD neither influenced pain thresholds nor self-report ratings, nor catastrophizing or mood. Only facial responses were significantly affected by ATD. ATD led to a decrease in pain-indicative as well as in pain-non-indicative facial responses to painful heat, compared to the control condition. CONCLUSIONS: Decrease in brain 5-HT synthesis via ATD significantly reduced facial responses to phasic heat pain; possibly due to (i) diminished disposition to display social behavior or due to (ii) decreased facilitation of excitatory inputs to the facial motor neuron.

The effect of induced optimism on early pain processing: indication by contact heat evoked potentials (CHEPs) and the sympathetic skin response (SSR).

Situationally induced optimism has been shown to influence several components of experimental pain. The aim of the present study was to enlarge these findings for the first time to the earliest components of the pain response by measuring contact heat evoked potentials (CHEPs) and the sympathetic skin response (SSR). Forty-seven healthy participants underwent two blocks of phasic thermal stimulation. CHEPs, the SSR and self-report pain ratings were recorded. Between the blocks of stimulation, the 'Best Possible Self' imagery and writing task was performed to induce situational optimism. The optimism manipulation was successful in increasing state optimism. It did, however, neither affect pain-evoked potentials nor the SSR nor self-report pain ratings. These results suggest that optimism does not alter early responses to pain. The higher-level cognitive processes involved in optimistic thinking might only act on later stages of pain processing. Therefore, more research is needed targeting different time frames of stimulus processing and response measures for early and late pain processing in parallel.

Counterirritation by Pain Inhibits Responses to and Perception of Aversive Loud Tones.

The application of a noxious stimulus reduces the perception of other noxious stimuli, which can be assessed by an experimental method called "counterirritation." The question arises whether this type of inhibition also affects the processing of other aversive (but not nociceptive) stimuli, such as loud tones. If aversiveness or, in other words, negative emotional valence qualifies a stimulus to be affected by counterirritation, the general emotional context may also play a role in modulating counterirritation effects. We involved 63 participants in this study (M age = 38.8, SD = 10.5 years; 33 males, 30 females). We tried to counterirritate their perceptual and startle reactions to aversively loud tones (105 db) by immersing the hand into a painful hot water bath (46°C) in two emotional valence conditions (i.e., a neutral and a negative valence block in which we showed either neutral pictures or pictures of burn wounds). We assessed Inhibition by loudness ratings and startle reflex amplitudes. Counterirritation significantly reduced both loudness ratings and startle reflex amplitudes. The emotional context manipulation did not affect this clear inhibitory effect, showing that counterirritation by a noxious stimulus affects aversive sensations not induced by nociceptive stimuli. Thus, the assumption that "pain inhibits pain" should be widened to "pain inhibits the processing of aversive stimuli." This broadened understanding of counterirritation leads to a questioning of the postulate of clear pain specificity in paradigms like "conditioned pain modulation" (CPM) or "diffuse noxious inhibitory controls" (DNIC).

Brain mechanisms associated with facial encoding of affective states.

Affective states are typically accompanied by facial expressions, but these behavioral manifestations are highly variable. Even highly arousing and negative valent experiences, such as pain, show great instability in facial affect encoding. The present study investigated which neural mechanisms are associated with variations in facial affect encoding by focusing on facial encoding of sustained pain experiences. Facial expressions, pain ratings, and brain activity (BOLD-fMRI) during tonic heat pain were recorded in 27 healthy participants. We analyzed facial expressions by using the Facial Action Coding System (FACS) and examined brain activations during epochs of painful stimulation that were accompanied by facial expressions of pain. Epochs of facial expressions of pain were coupled with activity increase in motor areas (M1, premotor and SMA) as well as in areas involved in nociceptive processing, including primary and secondary somatosensory cortex, posterior and anterior insula, and the anterior part of the mid-cingulate cortex. In contrast, prefrontal structures (ventrolateral and medial prefrontal) were less activated during incidences of facial expressions, consistent with a role in down-regulating facial displays. These results indicate that incidences of facial encoding of pain reflect activity within nociceptive pathways interacting or possibly competing with prefrontal inhibitory systems that gate the level of expressiveness.

How gender affects the decoding of facial expressions of pain.

OBJECTIVES: Gender has been suggested to play a critical role in how facial expressions of pain are perceived by others. With the present study we aim to further investigate how gender might impact the decoding of facial expressions of pain, (i) by varying both the gender of the observer as well as the gender of the expressor and (ii) by considering two different aspects of the decoding process, namely intensity decoding and pain recognition. METHODS: In two online-studies, videos of facial expressions of pain as well as of anger and disgust displayed by male and female avatars were presented to male and female participants. In the first study, valence and arousal ratings were assessed (intensity decoding) and in the second study, participants provided intensity ratings for different affective states, that allowed for assessing intensity decoding as well as pain recognition. RESULTS: The gender of the avatar significantly affected the intensity decoding of facial expressions of pain, with higher ratings (arousal, valence, pain intensity) for female compared to male avatars. In contrast, the gender of the observer had no significant impact on intensity decoding. With regard to pain recognition (differentiating pain from anger and disgust), neither the gender of the avatar, nor the gender of the observer had any affect. CONCLUSIONS: Only the gender of the expressor seems to have a substantial impact on the decoding of facial expressions of pain, whereas the gender of the observer seems of less relevance. Reasons for the tendency to see more pain in female faces might be due to psychosocial factors (e.g., gender stereotypes) and require further research.

The Effects of Recovery Sleep on Experimental Pain.

Recent research suggests that recovery sleep (RS) has the potential to restore pain sensitivity and modulation after hyperalgesia due to preceding sleep deprivation. However, it has not yet been systematically examined whether the restoration of these pain parameters is driven by sleep characteristics of RS. Thus, the present study assessed changes in experimental pain during RS after total sleep deprivation (TSD) to test whether RS parameters predicted the restoration of the pain system. Thirty healthy participants completed one night of habitual sleep, one night of TSD and a subsequent recovery night. At-home sleep during baseline and recovery was assessed using portable polysomnography and a questionnaire. Before and after each night pressure pain thresholds (PPTs), temporal pain summation (TSP) and conditioned pain modulation (CPM) were assessed. PPTs decreased after TSD and increased following RS, indicating a restoration of pain sensitivity after hyperalgesia. RS characteristics did not predict this restoration, suggesting other mechanisms (eg, changes in serotonergic activity) underlying the observed pain changes. TSP indicated a lack of effect of experimental sleep manipulations on excitatory processes whereas CPM lacked sufficient reliability to investigate inhibitory processes. Thus, results indicate moderate effects of sleep manipulations on pain sensitivity, but not on pain modulation. PERSPECTIVE: This article highlights the potential of recovery sleep to let pain thresholds return to normal following their decrease after a night of total sleep deprivation. In contrast, endogenous pain modulation (temporal pain summation, conditioned pain modulation) was not affected by sleep deprivation and recovery sleep.

The common interests of health protection and the economy: evidence from scenario calculations of COVID-19 containment policies.

We develop a novel approach integrating epidemiological and economic models that allows data-based simulations during a pandemic. We examine the economically optimal opening strategy that can be reconciled with the containment of a pandemic. The empirical evidence is based on data from Germany during the SARS-CoV-2 pandemic. Our empirical findings reject the view that there is necessarily a conflict between health protection and economic interests and suggest a non-linear U-shape relationship: it is in the interest of public health and the economy to balance non-pharmaceutical interventions in a manner that further reduces the incidence of infections. Our simulations suggest that a prudent strategy that leads to a reproduction number of around 0.75 is economically optimal. Too restrictive policies cause massive economic costs. Conversely, policies that are too loose lead to higher death tolls and higher economic costs in the long run. We suggest this finding as a guide for policy-makers in balancing interests of public health and the economy during a pandemic.

Effects of psychosocial stress and performance feedback on pain processing and its correlation with subjective and neuroendocrine parameters.

OBJECTIVES: Previous research on stress-induced pain modulation suggests that moderate psychological stress usually leads to hyperalgesia while more severe threat results in hypoalgesia. However, existing studies often lack suitable control conditions imperative to identify mere stress effects. Similarly, research mainly focused on pure anticipation of a social threat, not taking into consideration actual experiences of social evaluation. Therefore, we set out to investigate actual social up- and downgrading combined with a standardized stress paradigm to evaluate short-term and prolonged changes in pain perception and their potential association with neuroendocrine and subjective stress parameters. METHODS: We allocated 177 healthy women to four experimental conditions, either the standard version of the Trier Social Stress Test (TSST) followed by positive, negative or no performance feedback, or a well-matched but less demanding placebo version of the TSST. Stress responses were assessed with ratings, salivary alpha-amylase, and salivary cortisol. To capture putative effects of stress on pain, heat pain threshold, ratings of phasic heat pain stimuli, and conditioned pain modulation were measured. RESULTS: Despite a largely successful stress induction, results do not support a reliable influence of experimentally induced social stress-with or without subsequent performance feedback-on pain in women. Further, we found no clear association of pain modulation and changes in neuroendocrine or subjective stress responses. CONCLUSIONS: Our results contrast previous studies, which repeatedly demonstrated stress-induced hypo- or hyperalgesia. This might be due to methodological reasons as former research was often characterized by high heterogeneity regarding the applied stressors, low sample sizes, and lacking or inconclusive control conditions. Thus, our results raise the question whether pain modulation in women by experimental psychosocial stress might have been overestimated in the past. Future research is necessary, which should employ parametric stress induction methods including well-matched control tasks, taking into consideration the participants' gender/sex and the time course of the stress response relative to pain assessment. The study is registered as DRKS00026946 at 'Deutsches Register Klinischer Studien' (DRKS) and can be also found at the World Health Organization's search portal.

The Effect of Induced Optimism on Situational Pain Catastrophizing.

Background: There is broad evidence that optimism is associated with less pain, while pain catastrophizing leads to increased pain. The aim of this study was to examine whether experimentally induced optimism can reduce situational pain catastrophizing and whether this relation is moderated by dispositional optimism and/or dispositional pain catastrophizing. Methods: Situational pain catastrophizing during two thermal stimulations was measured in 40 healthy participants with the Situational Catastrophizing Questionnaire (SCQ). Between the two stimulations, the Best Possible Self (BPS) imagery and writing task was performed to induce situational optimism in the experimental group while the control group wrote about their typical day. Questionnaires were administered to assess dispositional optimism [Life Orientation Test-Revised (LOT-R)] and dispositional pain catastrophizing [Pain Catastrophizing Scale (PCS)]. Results: There was a significant interaction between the optimism induction and trait pain catastrophizing: the association of trait pain catastrophizing with state pain catastrophizing was weakened after the optimism induction. No overall effect of induced optimism on situational pain catastrophizing and no significant moderating influence of trait optimism were found. Conclusion: The state optimism induction apparently counteracted the manifestation of dispositional pain catastrophizing as situational pain catastrophizing. This implies that high trait pain catastrophizers may have especially benefitted from the optimism induction, which is in line with resilience models stressing the buffering role of optimism.

Automatic Coding of Facial Expressions of Pain: Are We There Yet?

INTRODUCTION: The experience of pain is regularly accompanied by facial expressions. The gold standard for analyzing these facial expressions is the Facial Action Coding System (FACS), which provides so-called action units (AUs) as parametrical indicators of facial muscular activity. Particular combinations of AUs have appeared to be pain-indicative. The manual coding of AUs is, however, too time- and labor-intensive in clinical practice. New developments in automatic facial expression analysis have promised to enable automatic detection of AUs, which might be used for pain detection. OBJECTIVE: Our aim is to compare manual with automatic AU coding of facial expressions of pain. METHODS: FaceReader7 was used for automatic AU detection. We compared the performance of FaceReader7 using videos of 40 participants (20 younger with a mean age of 25.7 years and 20 older with a mean age of 52.1 years) undergoing experimentally induced heat pain to manually coded AUs as gold standard labeling. Percentages of correctly and falsely classified AUs were calculated, and we computed as indicators of congruency, "sensitivity/recall," "precision," and "overall agreement (F1)." RESULTS: The automatic coding of AUs only showed poor to moderate outcomes regarding sensitivity/recall, precision, and F1. The congruency was better for younger compared to older faces and was better for pain-indicative AUs compared to other AUs. CONCLUSION: At the moment, automatic analyses of genuine facial expressions of pain may qualify at best as semiautomatic systems, which require further validation by human observers before they can be used to validly assess facial expressions of pain.

The induction of social pessimism reduces pain responsiveness.

OBJECTIVES: Past work has found that optimism reduces a person's responsiveness to pain, but the effects of pessimism are not clear. Therefore, we gave pessimistic forecasts of participants' future social life and measured changes in their pain responsiveness. In particular, some participants were told that they would end up alone in life. METHODS: Seventy-five subjects were investigated in three conditions (negative forecast, positive forecast, no forecast) for changes in pain threshold and pain tolerance threshold. Pressure pain induction was accomplished by either human- or machine-driven algometers. A randomly assigned bogus forecast promising either a lonely or a socially satisfying future was ostensibly based on a personality questionnaire and an emotional dot-probe task. As potential covariates, questionnaires assessing dispositional optimism (LOT-R), pain catastrophizing (PCS), and self-esteem (SISE) were given. RESULTS: Pain thresholds suggested a change toward unresponsiveness only in the negative forecast condition, with only small differences between the modes of pain induction (i.e., human or machine). The results for pain tolerance thresholds were less clear also because of limiting stimulation intensity for safety reasons. The covariates were not associated with these changes. CONCLUSIONS: Thus, people expecting a lonely future became moderately less responsive to pain. This numbing effect was not modulated by personality measures, neither in a protective fashion via dispositional optimism and self-esteem nor in a risk-enhancing fashion via trait pain catastrophizing. Alternative mechanisms of action should be explored in future studies.

Observing Pain in Individuals with Cognitive Impairment: A Pilot Comparison Attempt across Countries and across Different Types of Cognitive Impairment.

Facial expression is a key aspect in observational scales developed to improve pain assessment in individuals with cognitive impairments. Although these scales are used internationally in individuals with different types of cognitive impairments, it is not known whether observing facial expressions of pain might differ between regions or between different types of cognitive impairments. In a pilot study, facial responses to standardized experimental pressure pain were assessed among individuals with different types of cognitive impairments (dementia, mild cognitive impairment, Huntington's disease, and intellectual disability) from different countries (Denmark, Germany, Italy, Israel, and Spain) and were analyzed using facial descriptors from the PAIC scale (Pain Assessment in Impaired Cognition). We found high inter-rater reliability between observers from different countries. Moreover, facial responses to pain did not differ between individuals with dementia from different countries (Denmark, Germany, and Spain). However, the type of cognitive impairment had a significant impact; with individuals with intellectual disability (all being from Israel) showing the strongest facial responses. Our pilot data suggest that the country of origin does not strongly affect how pain is facially expressed or how facial responses are being scored. However, the type of cognitive impairment showed a clear effect in our pilot study, with elevated facial responses in individuals with intellectual disability.

Pain Processing in Cognitive Impairment and Its Association with Executive Function and Memory: Which Neurocognitive Factor Takes the Lead?

It is well established that individuals with cognitive impairment present with disturbed forms of pain processing of still unknown origin. As a neurocognitive factor, executive functions have become favored candidates for explanation. For further insights, we aimed at comparing executive functions and memory in their association with parameters indicating onset and escalation of pain perception. Subjective ratings of experimentally induced pressure pain applied in ascending series were assessed in older individuals with (N = 32) and without mild cognitive impairments (MCI) (N = 32). We investigated whether executive functioning (Trail Making Test-B (TMT-B), semantic fluency) or memory (word list and figure recall) were more closely linked to the onset and the escalation of pain. For the MCI group, a strong linkage between pain responses and the TMT-B could be found, i.e., poor test performance was associated with weak pain onset but strong pain escalation. The contribution of memory functions was less substantial and systematic. The prominent role of executive function for pain processing in individuals with MCI could be replicated by a test of cognitive flexibility. This lack of adaptability let individuals with MCI be less vigilant to pain at the beginning but allows for escalating pain in the further course. Thus, being first not sufficiently prepared and later overwhelmed as regards pain may be an early problem in MCI individuals with reduced executive functioning.

Assessment of effects of total sleep deprivation and subsequent recovery sleep: a methodological strategy feasible without sleep laboratory.

BACKGROUND: Sleep is critical for maintaining homeostasis in bodily and neurobehavioral functions. This homeostasis can be disturbed by sleep interruption and restored to normal by subsequent recovery sleep. Most research regarding recovery sleep (RS) effects has been conducted in specialized sleep laboratories, whereas small, less-well equipped research units may lack the possibilities to run studies in this area. Hence, the aims of the present study were to develop and validate an experimental protocol, which allows a thorough assessment of at-home recovery sleep after sleep deprivation. METHODS: The experimental protocol, comprising one night of baseline sleep (BL) at home, one night of monitored total sleep deprivation and a subsequent recovery night at home, was tested in a sample of 30 healthy participants. Subjects' fatigue and alertness were assessed prior to and after each night. Sleep at home (BL, RS) was objectively assessed using portable polysomnography. To check whether our at-home sleep assessments yielded results that are comparable to those conducted in sleep laboratories, we compared the sleep data assessed in our study with sleep data assessed in laboratory studies. RESULTS: Sleep parameters assessed during RS exhibited changes as expected (prolonged total sleep time, better sleep efficiency, slow wave sleep rebound). Sleep parameters of BL and RS were in line with parameters assessed in previous studies examining sleep in a laboratory setting. Fatigue normalized after one night of RS; alertness partly recovered. CONCLUSIONS: Our results suggest a successful implementation of our new experimental protocol, emphasizing it as a useful tool for future studies on RS outside of well-equipped sleep laboratories.

Pain processing in older adults with dementia-related cognitive impairment is associated with frontal neurodegeneration.

Experimental pain research has shown that pain processing seems to be heightened in dementia. It is unclear which neuropathological changes underlie these alterations. This study examined whether differences in pressure pain sensitivity and endogenous pain inhibition (conditioned pain modulation (CPM)) between individuals with a dementia-related cognitive impairment (N=23) and healthy controls (N=35) are linked to dementia-related neurodegeneration. Pain was assessed via self-report ratings and by analyzing the facial expression of pain using the Facial Action Coding System. We found that cognitively impaired individuals show decreased CPM inhibition as assessed by facial responses compared to healthy controls, which was mediated by decreased gray matter volume in the medial orbitofrontal and anterior cingulate cortex in the patient group. This study confirms previous findings of intensified pain processing in dementia when pain is assessed using non-verbal responses. Our findings suggest that a loss of pain inhibitory functioning caused by structural changes in prefrontal areas might be one of the underlying mechanisms responsible for amplified pain responses in individuals with a dementia-related cognitive impairment.