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Reduced pain inhibition is associated with reduced cognitive inhibition in healthy aging

Marouf, Rafika,b; Caron, Stéphaneb,c; Lussier, Maximeb,d; Bherer, Louisb,e; Piché, Mathieub,f,g; Rainville, Pierrea,b,c,f,h,*

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doi: 10.1016/j.pain.2013.11.011
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Abstract

1. Introduction

Over 38% of older persons living in health care institutions and 27% living in private households are affected by chronic pain [29]. In addition, a number of cognitive and neurophysiological changes occur during healthy aging, which may contribute to the development of chronic pain conditions. Age-related cognitive changes include a decline in episodic memory [26], decreased working memory [32], reduced attention resources (especially selective attention [5] and sustained attention [11]), as well as decreased inhibitory functions [34]. In accordance with these behavioural changes, there is electrophysiological evidence of age-related decline in inhibitory functions related to sensory [24] and cognitive [41] processes. However, a closer examination of these results indicates that age-related effects on executive functions are much less pervasive than generally assumed, and are found more clearly in conditions involving divided attention or task-switching (for review see [37]).

Alteration of endogenous pain inhibition processes has been shown in older persons, and this may contribute to the frequency of chronic pain in the elderly. In these studies, the integrity of pain inhibition mechanisms was assessed using heterotopic noxious counter-stimulation (HNCS), involving the inhibition of pain by a competing noxious stimulus applied on a different part of the body. Washington et al. were the first to report age differences in HNCS analgesia and increased sensitivity to pain in older adults (mean age, 78years old) compared with young adults (mean age, 23years old) [40]. In this study, the threshold of pain induced by electrical stimulation and thermal CO2 laser was increased after hand immersion in painful cold water in both groups, but less so in the older group. Edwards et al. also suggest an age-related decrease in the efficacy of descending inhibitory controls [10]. In this study, older adults (n=48, mean age=63.1years, range=55-67years) showed facilitation rather than inhibition of thermal pain during concurrent noxious cold stimulation, while younger adults (n=45, mean age=21.6years, range=18-25years) showed a reduction in thermal pain ratings during cold pain. A subsequent study examined age-related differences in diffuse noxious inhibitory controls over a wide age continuum and observed decreased endogenous pain modulation starting from middle-aged (between 40 and 55years old) compared with younger subjects (between 20 and 35years old), whereas pain inhibition was abolished in older persons (between 60 and 75years old) [20]. Another study reported that, compared to younger persons (20-49years), older persons (56-77years of age) failed to demonstrate HNCS analgesia and even showed heat pain facilitation during HNCS (cold water foot immersion) [30].

HNCS and Stroop involve stimulus competition and solicit top-down regulation processes underlying inhibition. We hypothesize that decreased HNCS analgesia is related to a decrease in cognitive inhibition as evidenced by the Stroop test as a part of a global decline in inhibitory functions with age. To test this hypothesis, the present study assesses the correlation between these 2 declines and examines the specificity of the association by controlling age-related effects not involving inhibitory processes.

2. Materials and methods

2.1. Ethics approval

All experimental procedures conformed to the standards set by the latest revision of the Declaration of Helsinki and were approved by the Research Ethics Board of “Institut universitaire de gériatrie de Montréal.” All participants gave written informed consent, acknowledging their right to withdraw from the experiment without prejudice and received compensation of $50 for their travel expenses, time, and commitment. The study consisted of a session of 120minutes, in which questionnaires were administered, thresholds of the RIII reflex were determined, the modulation of pain and RIII-reflex amplitude by HNCS was performed, and the Stroop test was completed.

2.2. Participants

Forty-five healthy volunteers were recruited among participants from the database of “Institut universitaire de gériatrie de Montréal,” and by advertisement on the campus of “Université de Montréal.” Participants were excluded if they presented chronic pain syndromes, psychiatric disorders, neurologic disorders, metabolic disorders (diabetes), vascular disorders (eg, inferior members arteriopathy), or used medication that could alter pain perception and modulation 2weeks prior to the experiment, including antihypertensives, anxiolytics, antidepressants, and other psychotropic agents. During the screening telephone call, participants were asked to abstain from consuming alcohol at least 1day before experimentation, and refrain from consuming tea and coffee on the day of the experiment. One participant was excluded because he could not tolerate the experimental procedures. Two groups of participants were tested, including 21 young persons, 10 women and 11 men, ranging between 18 and 46years of age (mean age 28.8±9.1years), and 23 older persons, 13 women and 10 men, ranging between 56 and 75years of age (mean age 62.9±5.4years). Based on a self-rated audition and vision questionnaire, all participants reported normal or corrected perceptual abilities (see Table 1).

T1-8
Table 1:
Demographic characteristic, baseline cognitive functioning, RIII, and pain threshold.

2.3. Experimental design

This study relied on a mixed design to examine the effects of HNCS on RIII-reflex amplitude and acute shock pain between 2 groups of participants: younger persons (n=21) and older persons (n=23). Groups were also compared on inhibition (Stroop test) and psychological factors (see below). Between RIII-threshold determination and HNCS, participants were also asked to complete questionnaires, the similitude test, and the digital symbol-coding test (subtests of the Wechsler Adult Intelligence Scale [WAIS] III) [25]. This allowed participants to rest from electrical stimulation for a period of approximately 15minutes.

2.4. Painful electrical stimulation

Transcutaneous electrical stimulation (trains of 10×1-ms pulses at 333Hz) was delivered with a custom-made isolated constant current stimulator triggered by a train generator (Grass Medical Instruments, Quincy, MA, USA) and controlled by a computer running E-Prime2 (Psychology Software Tools, Sharpsburg, PA, USA). Degreased skin over the retromalleolar path of the right sural nerve was stimulated by a pair of custom-made surface electrodes (1cm2; 2-cm interelectrode distance). The RIII-reflex threshold was determined using the staircase method, including 4 series of stimuli of increasing and decreasing intensity [28,43]. Each series always began with an intensity of 1mA and was followed by increments of 1mA until the subject reported pain intensity of 70 on the 0-100 pain scale (see below). Stimulus intensity was then decreased by steps of 1mA. The individual's stimulus-response plot was then created, and the RIII-threshold was determined as the intensity producing a clear response in at least 50% of trials (ie, above noise level according to the individual stimulus-response plot). The intensity of stimulation was then adjusted individually at 120% of the RIII-reflex threshold, and a series of 10 stimulations was administered to insure stability of responses (otherwise threshold assessment was repeated). Stimulus intensity remained constant at 120% of the RIII threshold for the remaining of the experiment. The mean intensity at which the subject began to feel pain determined the pain threshold, and the mean of the stimulus intensity required to produce a rating of 70 on the 0-100 scale was defined as the strong pain level (pain-70). These measures allowed assessing baseline group differences in nociception and pain perception.

2.5. RIII-reflex measure and analyses

Electromyography (EMG) of the short head of the biceps femoris was recorded with a pair of surface electrodes (EL-508, Biopac Systems, Inc., Goleta, CA, USA). The signal was amplified 1000 times, band-pass filtered (100-500Hz), digitized, and sampled at 1000Hz. EMG data were analyzed using Acqknowledge 4.1 (Biopac Systems, Inc.). The raw EMG recordings were transformed using the root mean square with a window of 10ms. The resulting signal was integrated between 90 and 180ms after the stimulus onset to quantify RIII-reflex amplitude to each shock. These values were normalized (z-score) across all trials within subjects and averaged for each condition (15 stimulations each) to assess the effects of HNCS.

2.6. Heterotopic noxious counter-stimulation (HNCS)

The HNCS paradigm lasted 13minutes and included 80 electrical stimuli administered with an interstimulus interval of 6seconds (Fig. 1A). The first 5 stimuli were excluded from the analyses to control for the rapid habituation effect occasionally observed on the first few trials of a series of RIII measurements. The subsequent 75 stimuli were distributed equally in 5 sequential conditions with an interval of 12seconds between conditions: baseline (n=15), HNCS (n=15), and 3 blocks of recovery after removing HNCS (3 times n=15). HNCS was produced by placing an ice pack on the contralateral forearm for 2minutes (surface temperature about −13°C). Shock pain was rated after the last shock of each experimental block. Cold pain was also rated at the end of the HNCS block. The HNCS effect on the RIII was calculated by subtracting the mean RIII-reflex amplitude of the HNCS block from that of the baseline block.

F1-8
Fig. 1.:
(A) Heterotopic noxious counter-stimulation (HNCS) paradigm. A series of 80 electric shocks was delivered on the skin overlying the right sural nerve every 6 seconds, distributed in 5 conditions: 1) prebaseline, 2) baseline, 3) HNCS, 4) recovery 1, 5) recovery 2, and 6) recovery 3. HNCS was applied for 2 minutes during the series of electric shocks by putting an ice pack (temperature around −13°C) on the contralateral forearm. Shock pain was rated on a visual analogue scale (VAS) after the last shock of each experimental block. Cold-pain rating was collected at the end of the HCNS block. (B) Stroop task paradigm. Four conditions (reading = T1, naming = T2, inhibition = T3, and switching = T4) were performed in 60 trials each. The subject has to identify the color of the ink of the word by pressing the button corresponding to the same color in all conditions, except in the switching condition where he has to press the button corresponding to the meaning of the word when this one is preceded by a rectangle. In the switching condition, only the inhibition trials occurring after a switching trial in the same condition were taken (T4a) to calculate the interference.

2.7. Pain ratings

Participants rated shock and cold pain intensity verbally using visual-numerical (0-100) pain-rating scales displayed horizontally on the wall facing participants with verbal anchors at the left (0=no pain) and right extremities (100=extremely intense). The HNCS effect on pain rating was calculated by subtracting the pain rating value of the HNCS block from the pain rating value of the baseline block.

2.8. Questionnaires

State and trait anxiety was assessed using the validated French version of the Spielberger State-Trait Anxiety Inventory [39]. Pain catastrophizing was assessed using the French version of the Pain Catastrophizing Scale (PCS) [9]. Subjects completed questionnaires prior to starting the pain tests and were asked to do so in reference to previous pain events. The elderly volunteers were screened for cognitive impairment using the Mini-Mental State Examination [12]. A score of 26+ was required for inclusion in the study (all recruited volunteers scored 27+). Depression was assessed using the French version of the Beck Depression Inventory [3] for the young group and by the Geriatric Depression Scale for the elderly group [4,47].

2.9. Modified Stroop test

The session ended with a modified computerized Stroop task [35] involving 4 different conditions (reading, naming, inhibition, switching; Fig. 1B). In the reading condition (T1), participants read words meaning colors displayed in type fonts of the congruent color (red, blue, yellow, or green). In the color-naming condition (T2), participants named the colors of noncolor words displayed in one of the same 4 colors (neutral condition). The inhibition condition (incongruent condition; T3) consists of naming the color of the font of incongruent color-words (eg, the word RED displayed in green). In the switching condition (T4), the participant named the color in which the incongruent color-word was displayed when the word is preceded by a cross, similarly to the inhibition condition, but read the word when it was preceded by a rectangle. For each condition, participants were instructed to execute the task as fast and as accurately as possible. The first 2 conditions (T1-reading and T2-neutral naming) tap on processing speed, the third condition involves inhibition (T3-incongruent naming), and the fourth involved switching and inhibition (T4a-alternation repeated color). Interference has been previously shown to be particularly enhanced in these inhibition trials of the switching condition [37,42]. A maximum of 3 naming or reading trials were presented consecutively in T4, and performance was further decomposed according to the specific trial condition, distinguishing the initial switching trials reflecting the change in task-set from the consecutive trials of each condition. The analysis of the Stroop interference focused on the trials that follow the first of a series of inhibition trials (ie, the second, or second and third, consecutive inhibition trials after switching in T4 condition were labeled T4a). Performance in these T4a trials reflect more the inhibition process within the context of switching, without including the large switching effect observed in the first switching trial of a series in the same condition.

The reaction time (RT) was extracted and the mean value of the 60 trials for each task was calculated after removing the 4 first trials (allowing adaptation) (Table 2). In order to calculate the value corresponding to the interference in the fourth condition, the mean RT of the naming task (T2), serving as control, was subtracted from the mean RT of the inhibition trials (T4a-alternation repeated color) of the switching task (T4). This index reflects the cost of cognitive inhibition (Stroop interference) in the context of task-switching, which was previously shown to be particularly sensitive to aging effects on executive function (see [37]).

T2-8
Table 2:
Stroop performance measures.

2.10. Statistical analyses

All results are expressed as mean±SD. The data were analyzed by SPSS v17 (SPSS Inc., Chicago, IL, USA) with significance thresholds set to P≤0.05. Two 2×5 mixed-model analyses of variance (ANOVAs) were performed, entering the age group as the between-subject variable and the 5 successive measures of pain and RIII reflex as the within-subject factor. Planned contrasts were then used to test a priori hypotheses and decompose significant effects of HNCS between groups. Sphericity was tested using Mauchly's test and Type I error was controlled by adjusting the degrees of freedom using the Greenhouse-Geisser correction.

For the Stroop task, repeated-measures ANOVAs were also performed within subject to assess the changes in RT between tasks. Planned contrasts performed to assess the interaction between GROUPS×TASK. Effect size was assessed with partial eta-squared (η2). Pearson correlations were performed across all subjects between age, the Stroop effect, and the modulatory effect of HNCS on pain and on the RIII reflex. Partial correlations were performed to test mediation, when appropriate.

3. Results

3.1. Psychological measures

Characteristics of participants are reported in Table 1. Groups were comparable on education, PCS, depression, state and trait anxiety, and the similitude test. However, the younger group performed slightly faster than the older group in the digit symbol coding [DSC: t(42)=2.18, P=0.035, η2=.10; see Table 1].

No significant correlation was found between HNCS effect on RIII reflex or pain rating and depression, the PCS, or the State-Trait Anxiety Inventory (all r<.20, P>0.1).

3.2. Pain and RIII thresholds

Older persons showed a slightly lower pain threshold compared with younger persons [t(34.4)=2.16; P=0.04, η2=.09; see Table 1]. However, no significant difference was observed between groups for the RIII-reflex threshold [t(42)=.86; P=0.39] and the pain-70 level [t(42)=.053; P=0.59].

3.3. Older persons showed reduced pain modulation during HNCS

Pain ratings were compared between blocks and across groups by a mixed-model ANOVA. Fig. 2 shows that pain was significantly modulated between blocks, and this effect was significantly different between groups [interaction: F(3.02,126.8)=3.4, P=0.019, η2=.076, observed power=.76]. Planned contrasts revealed that for older persons, HNCS did not significantly affect shock pain in comparison to baseline [F(1,22)=.3, P=0.5). In contrast, younger persons showed a significant pain reduction during HNCS compared with baseline [F(1,20)=15.03, P=0.001, η2=.43, observed power=.96]. Consistent with the significant interaction term of the ANOVA, this pain reduction was significantly greater compared with older persons [F(1,43)=14.2, P<0.001, η2=.25, observed power=.95]. Pain ratings returned to baseline levels in the first recovery block in younger persons [F(1,42)=1.4, P=0.24], indicating no significantly persistent analgesic effects. All effects remained significant after controlling for differences in baseline pain ratings, including the key interaction between BLOCK and GROUP [F(3.02,126.8)=3.3, P=0.023, η2=.074, observed power=.74]. Pain rating of the conditioning stimulus (ice pack) did not differ between the young (Mean=44.76, SD=33.22) and the elderly participants (Mean=46.30, SD=28.25; t(42)=−.166; P=0.87]. There was no significant correlation between the pain rating of conditioning stimulus and the magnitude of the HNCS on pain rating of the test stimulus (r=−.245; P=0.1). Covariance controlling for individual differences in pain rating of the conditioning stimulus did not change the statistical conclusions of the above analysis.

F2-8
Fig. 2.:
Shock pain ratings during successive blocks (SE bars). Each block lasts 2 minutes. Pain was significantly modulated between blocks, and this effect was significantly different between groups. Heterotopic noxious counter-stimulation (HNCS) (block 2) produced strong analgesia in younger but not in elderly patients (see statistics in the main text). VAS, visual analogue scale.

3.4. Older persons showed reduced RIII-reflex modulation during HNCS

Mean RIII-reflex amplitude was compared between blocks and across groups by a mixed-model ANOVA (Fig. 3). There was a main effect of BLOCK [F(3.13,131.23)=23.06, P<0.001, η2=.35, observed power=1.0], but no main effect of GROUP [F(1,42)=2.8, P=0.10]. In addition, there was a marginal interaction between BLOCK and GROUP [F(3.13,131.23)=2.6, P=0.053, η2=.06, observed power=.64]. Planned contrasts based on our prior hypothesis revealed that the magnitude of RIII inhibition during HNCS was significantly larger in young compared to older participants [F(1,42)=4.9, P=0.032, η2=.10, observed power=.58]. These effects remained significant when covarying with the pain rating of the conditioning stimulus (all Ps<0.05), and the key interaction BLOCK by GROUP also reached significance (P=0.49). Follow-up within-group analyses showed that HNCS did not significantly affect RIII-reflex amplitude in older persons in whom the mean response increased slightly during HNCS [F(1,42)=1.2, P=0.3]. In contrast, younger persons showed a marginal decrease of RIII-reflex amplitude during HNCS compared with baseline [F(1,42)=4.0, P=0.053, η2=.17, observed power=.5]. RIII-reflex amplitude did not recover to baseline values during recovery blocks (all Ps<0.05) and showed a steady decline until the last block. This pattern suggests a steady habituation of the RIII in both groups during the recovery phase. Although the inhibitory effect produced by HNCS on the RIII is confounded with this general habituation effect in the younger group, the group difference in the second block is consistent with a reduction of RIII inhibition during HNCS in older participants.

F3-8
Fig. 3.:
Comparison of mean RIII-reflex amplitude (expressed by z score) between blocks and across groups (SE bars). Heterotopic noxious counter-stimulation (HNCS) did not significantly affect RIII-reflex amplitude in comparison to baseline for older persons. In contrast, younger persons showed a decrease of RIII-reflex amplitude during HNCS compared with baseline (see statistics in main text).

3.5. The Stroop effect was stronger in the context of switching in the elderly

In the Stroop task, performance showed a significant main effect of condition [F(1.73,73)=208.8, P<0.001, η2=.83, observed power=1.0], reflecting a gradual RT increase between each of the 4 conditions (reading<color-naming<inhibition condition<inhibition in the switching condition; Fig. 4, Table 2). In addition, there was a significant main effect of GROUP [F(1.73,73)=8.02, P=0.001, η2=.16, observed power=.93], with the older subjects responding more slowly. There was no group effect when the interference was calculated by subtracting the RT of reading or naming from the RT of the inhibition condition [T3-T1: F(1)<.1, P>0.9; T3-T2: F(1)<.1, P>0.9]. However, there was a group effect when the RT of the reading or the naming condition was subtracted from the RT of inhibition trials of the switching condition [T4a-T1: F(1)=7.28, P=0.01, η2=.15, observed power=.75; T4a-T2: F(1)=8.28, P<0.01, η2=.17, observed power=.80; see Table 2]. This is consistent with the notion that cognitive inhibition in the context of switching is highly sensitive to aging.

F4-8
Fig. 4.:
Mean (SD) reaction times in each of the 4 conditions of the Stroop task in the young and old participants: reading (T1), naming (T2), inhibition (T3), and switching (T4). The inhibition trials of the switching condition are reported separately (T4a). Note the very large increase in the inhibition trials in the context of switching (T4a) compared to the inhibition condition alone (T3). This effect is significantly larger in the elderly (see Table 2 for detailed statistics contrasting groups).

3.6. Correlations between age, Stroop effect, pain modulation and RIII-reflex modulation

To assess the association between age, cognitive interference (T4a-T2), and both changes in pain ratings and descending modulation, differences between baseline and HCNS in pain ratings and RIII-reflex amplitude were calculated and analyzed using Pearson's correlations. Results showed that analgesia (reduced pain ratings) decreased with age (r=−.42, P=0.004; note that the Pearson correlation testing age effects are partly redundant with the group effect in ANOVA, as reported above). Consistent with the hypothesis, HNCS analgesia (ratings) was generally lower in subjects showing larger cognitive interference; however, this effect did not reach significance (r=−.23, P=.13) (Fig. 5A). Inhibition of the RIII reflex also decreased with age (r=−.39, P=0.014), but this effect was completely decoupled from the changes in pain (r=.07, P=0.6), suggesting that these modulatory effects rely on separate processes in the present study. Additional correlation analyses performed within each age group did not reach significance.

F5-8
Fig. 5.:
(A) The negative correlation between heterotopic noxious counter-stimulation (HNCS) analgesia and the Stroop effect (T4a-T2) did not reach significance across all subjects or within groups. (B) The scatter plot illustrates that the cognitive inhibition (Stroop effect = interference = T4a-T2) was negatively associated with changes in RIII-reflex amplitude induced by HNCS across all subjects (r-values reported on graph). The correlations within groups were not significant: younger (r = −.293, P = 0.197), elderly (r = −.188, P = .391). VAS, visual analogue scale.

Cognitive interference also increased with age (r=.41, P=0.005) and was significantly associated with the reduction of HNCS inhibitory effects on the RIII reflex across all subjects (r=−.34, P=0.025) (Fig. 5B). However, Pearson correlations between HNCS effect on RIII and Stroop interference effect did not reach significance when tested within each group: young (r=−.293, P=0.197); elderly (r=−.188, P=0.391) (Fig. 5). Similarly, a partial correlation controlling for the age groups did not reach significance (r=−.238, P=0.124). Based on these results alone, the association between cognitive interference and HNCS effect may reflect an effect of age on inhibitory processes.

In order to control for a putative nonspecific effect associated with age, we performed additional analyses based on 2 performance measures not involving inhibition but affected by aging: the reaction time of the reading and naming conditions. These 2 measures are significantly influenced by age (Ps<0.01; see Table 2), as one would expect with many variables, including those irrelevant to inhibitory process. However, the effect of HNCS on the RIII did not correlate significantly with performance in the naming (r=−.137, P=0.376) or the reading condition (r=−.112, P=0.471). Notably, the association between cognitive interferences and HCNS inhibitory effect on the RIII found across all participants (see above) also remained significant after controlling for the general slowing observed in RT in the elderly (covariance with naming RT in task 2: r=−.315, P=0.036; covariance with reading RT in task 1: r=−.321, P=0.040). In contrast, this correlation between the increased cognitive interference and the reduced RIII inhibition was no longer significant after controlling for age (r=−.22, P=0.16), consistent with the hypothesized mediation by a common age-related mechanism involving inhibition.

4. Discussion

4.1. Effects of age on pain perception

Most previous studies reported an increase of the pain threshold with age (for review, see [13]). This may be explained by the peripheral and central changes occurring with aging. It is well established that there is a decrease in the number of the nociceptive fibres [8], and a decrease in the transmission speed of nociceptive impulses with aging [1]. However, there are other studies describing either a decrease or no age effect on pain threshold, depending on the stimulus [22]. Many factors could influence age-related effect on pain threshold such as the integrity of the skin, the stimulus modality, and duration. In the present study, a decrease in pain threshold was found in elderly compared to young participants. When considering the effect of age on pain tolerance, a very different pattern of results emerges, with either no age-related changes (thermal and electrical pain), consistent with our results in the upper range of the pain scale (pain-70), or a decrease (pressure pain) over the lifespan (for review, see [21]).

4.2. Pain modulation and aging

In agreement with the literature, we observed that HNCS analgesia was lower for older adults. Reduction of pain modulation associated with age has been proposed to be due to changes in several descending inhibitory systems that could contribute to the greater prevalence of pain in older age [14]. Consistent with this, decreased endogenous analgesia was reported as a risk factor in the development of chronic pain [46]. In that study, less effective endogenous analgesia in a pain-free state before a thoracic surgery was associated with the development of postsurgical chronic pain. Pain inhibitory systems can be divided into opioid-dependent and non-opioid-dependent, which operate via neural or hormonal mechanisms. The μ-opioid receptors and their endogenous ligands are involved in the regulation of sensory and affective components of the pain experience [49]. In addition, it was shown that there is an age effect on μ-opioid receptors [48]. Several animal studies have documented a general age-related decline in the neural opioid and nonopioid analgesic mechanisms [15,17]. These changes may explain the behavioural and neurophysiological age-related effects reported in the present study.

4.3. RIII-reflex modulation and aging

The RIII reflex is interesting because it is an important objective tool to assess spinal nociceptive processes in humans [33,45]. In normal subjects, a close correlation exists between the threshold of the reflex and the pain threshold [43], although there are examples of a dissociation between the 2 measures. In healthy volunteers, RIII-reflex amplitude is strongly decreased by HNCS through a spinal-bulbo-spinal loop [2,7,31], consistent with opioid-dependent diffuse noxious inhibitory controls (DNICs) described in the rat [23]. Moreover, inhibition of the RIII reflex by HNCS can be blocked by low doses of an opioid antagonist (naloxone) [44]. Consequently, reduced RIII-reflex modulation by HNCS with age could be associated with functional changes at different levels of the neuraxis, and may involve changes in opioidergic neuromodulation [48]. Even though this study did not show the expected return to baseline after counter-stimulation, suggesting a steady habituation, the difference between the 2 groups in the HNCS block is consistent with age-related difference in HNCS modulation.

4.4. Cognitive inhibition and aging

Considering the Stroop effect and aging, there is some controversy. Some studies support the general slowing theory (see [38]), while others provide evidence that beyond the general slowing occurring with age, there is a specific age-related decline of inhibitory process involved in the suppression of lexical-semantic information in the Stroop task [41]. In addition, some functional magnetic resonance imaging studies report greater activation in older individuals during the Stroop task within several brain regions involved in executive control, such as the left inferior frontal gyrus [19]. Another study showed that middle-aged subjects (compared to young) were generally slowed, but may not show increased interference [49]. However, this study also showed age-related activation increases in several task-related brain regions: the inferior frontal junction area, and regions in the inferior frontal gyrus. The authors interpreted these changes as stronger dependence of the older subjects on compensatory strategies [50]. Results of the present study show that older subjects are slower than younger subjects in all conditions of the Stroop. There was no difference between groups in the interference indices comparing the inhibition condition to the naming or reading condition. However, a significantly larger increase in the interference effect was observed in the older subjects in the switching condition (see Table 2). This is consistent with previous observation that aging-related increase in interference is magnified in the context of task-switching due to increased cognitive demands [16,37].

4.5. Is there a general decline of inhibition with aging?

There is some evidence that the inhibitory control of pain decreases with aging [10,20,30,40] and that some cognitive functions, including inhibition, also decline with aging [16,34,37,41]. In our study, we found a significant correlation between the decrease of the amplitude of the RIII reflex induced by the HNCS and the Stroop effect. This correlation was explained statistically by age but not by the nonspecific slowing of RTs found across all tasks (partial correlations). This is consistent with the mediation of both phenomena by a common underlying mechanism involving inhibition and related to aging. However, the magnitude of HNCS analgesia was not associated with the Stroop effect or the magnitude of changes in RIII-reflex amplitude. This suggests that the modulation of pain and RIII-reflex amplitude may rely on partly distinct mechanisms.

We have previously reported that changes in pain and RIII reflex during HNCS are associated with partly distinct brain networks [27]. Interestingly, the magnitude of the HNCS inhibitory effect on the RIII-reflex amplitude was predicted by the magnitude of the brain stem response to the tonic pain stimulus in the periaqueductal gray matter. Furthermore, the periaqueductal gray response was strongly associated with a distributed network involving peaks in the lower pons and rostroventral medulla, as well as extended clusters in the lateral and medial prefrontal cortices. Notably, this network included areas previously associated with cognitive inhibition and with the age-related increase in cognitive interference (eg, ventrolateral prefrontal cortex [6,36]). Although pain inhibition and Stroop inhibition certainly rely on partly distinct mechanisms, the association between RIII inhibition during HNCS and the Stroop effect suggests that an overall decline in the efficacy of these inhibitory systems might occur during normal aging. The Stroop task involves a competition between the automatic lexical-semantic processing of the words and color naming, while HNCS involves the rivalry between competing noxious stimuli. We suspect that HNCS effects on pain and the RIII reflex may involve cycles of switching of attention between the 2 competing streams of sensory-affective processing triggered automatically by the tonic and the phasic pain stimuli. However, this spontaneous switching-related effect on the RIII reflex may be blocked when task instructions emphasize the top-down attention to one of the 2 stimuli (see the experimental paradigm of Ladouceur et al. [18]) This implies that age-related effects on HNCS must be further explored using paradigms taking into account the potential interactions between attention and switching processes. This association between 2 apparently different tests (Stroop and HNCS) may reflect age-related changes in the dynamic interaction between prefrontal executive systems sub-serving task-switching processes and those involved in attention and inhibition of automatic responses.

4.6. Study limitations

One limitation regarding HNCS analgesia is that, contrary to the pain ratings, the RIII reflex did not show the expected return to baseline after counter-stimulation. This pattern suggests a steady habituation of the RIII reflex in both groups during the recovery phase. Although the inhibitory effect produced by HNCS on the RIII reflex is confounded with this general habituation effect in the younger group, the group difference in the second block is consistent with a reduction of RIII inhibition during HNCS in older participants. Another limitation is that our study is a cross-sectional study of healthy aging comparing the target population with younger controls. A longitudinal design would be ideal, but this obviously poses major feasibility difficulties.

4.7. Conclusions

The present study is the first to examine the effects of normal aging on HNCS analgesia using a measure of spinal nociceptive transmission. It shows a decrease of inhibitory effects of HNCS on pain perception and spinal nociception with healthy aging. The decrease of HNCS effect on RIII reflex was significantly correlated with a decrease in the efficacy of cognitive inhibition processes with aging. Together, these results suggest an overall decline of inhibition systems occurring with aging. This study further provides ground for future investigations of the cerebral mechanisms underlying the effect of normal aging on pain control and cognitive executive processes.

Conflict of interest statement

The authors have no conflict of interest in relation to this work.

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Keywords:

Pain; Aging; DNIC; RIII reflex; Cognitive inhibition

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