Autonomic responses and pain perception in Alzheimer's disease.

We analysed the effects of electrical noxious stimulation on the autonomic nervous system of Alzheimer's disease (AD) patients who were assessed by means of the Mini Mental State Examination test (MMSE). To do this, we used electrical stimuli at two different intensities: just above pain threshold and twice pain threshold. We recorded heart rate and systolic blood pressure by using conventional electrocardiography and finger photo-plethysmography. When a pain stimulus just above threshold was delivered, AD patients were found to have blunted autonomic responses compared to controls of the same age. Similarly, prestimulus expectation produced a less pronounced increase of the responses in AD patients compared to the controls. However, when the painful stimulus was increased to twice the pain threshold, the systolic blood pressure increase of AD patients did not differ from the controls, whereas heart rate increase was still slightly diminished. By contrast, pain perception was similar in the two groups when the stimulus was at pain threshold, whereas it was blunted in AD patients when the stimulus was twice the pain threshold. These findings show that in AD mild noxious stimulation produces blunted autonomic responses and normal pain perception, whereas strong noxious stimulation produces quasi-normal autonomic responses and blunted pain perception. These results indicate that AD patients have an increased threshold for both autonomic activation and pain tolerance.     

Pain reactivity in Alzheimer patients with different degrees of cognitive impairment and brain electrical activity deterioration

Pain perception and autonomic responses to pain are known to be altered in dementia, although the mechanisms are poorly understood. We studied patients with Alzheimer's disease (AD) whose cognitive status was assessed through the Mini Mental State Examination test and whose brain electrical activity was measured by means of quantitative electroencephalography. After assessment of both cognitive impairment and brain electrical activity deterioration, these patients underwent sensory measurements in which the minimum stimulus intensity for both stimulus detection and pain sensation was determined. In addition, heart rate responses to pain threshold x 1.5 were recorded. We found that neither stimulus detection nor pain threshold was correlated to cognitive status and brain electrical activity decline. By contrast, we found a correlation between heart rate responses and deterioration of both cognitive functions and brain electrical activity. In particular, the heart rate increase after pain stimulation was correlated to the presence of slow brain electrical activity (delta and theta frequencies). This correlation was also found for the anticipatory heart rate increase just before pain stimulation. These results indicate that pain anticipation and reactivity depend on both the cognitive status and the frequency bands of the electroencephalogram, whereas both stimulus detection and pain threshold are not affected by the progression of AD. These findings indicate that, whereas the sensory-discriminative components of pain are preserved even in advanced stages of AD, the cognitive and affective functions, which are related to both anticipation and autonomic reactivity, are severely affected. This sensory-affective dissociation is well correlated with the neuropathological findings in AD.     

Effects of acute postoperative pain on catecholamine plasma levels, hemodynamic parameters, and cardiac autonomic control

Postoperative pain is often stated to be a significant contributor to a sympathetic stress response after surgery. However, hardly any evidence has been published to support this assumption. Hence it was the aim of this trial to investigate the relationship between postoperative pain and hemodynamic, endocrine, and autonomic parameters. A total of 85 postoperative patients in the recovery room were repeatedly asked to rate their pain on a numeric rating scale (NRS). Concurrently, the parameters of heart rate variability (HRV) were analysed, and mean arterial pressure (MAP), heart rate (HR) and respiration rate (RR) were recorded. Pain was categorized into no, mild, moderate, and severe. Blood samples were taken for epinephrine (EPI) and norepinephrine (NE) plasma level assessment at the time of recovery room admission and discharge, and each time pain was found decreased in categorized severity. A total of 239 pain readings were obtained. None of the investigated parameters correlated with NRS scores. NE was higher at NRS 5 to 10 vs. NRS 0 to 4 (mean [SEM]: 1009 [73] pg/mL vs. 872 [65] pg/mL; P<0.01). This was also found for MAP, but not for EPI or the parameters of HRV, HR, and RR. In contrast to common belief, the severity of postoperative pain does not appear to be associated with the degree of sympathetic stress response after surgery, and other factors such as surgical trauma may be more important. Importantly, the absence of signs of sympathetic stimulation cannot be seen as a guarantee for the absence of significant pain.     

Heart rate changes as an autonomic component of the pain response

Autonomic variables have been recommended as measures of the affective-motivational component of the pain response in objective algesimetry. In the present study components of heart rate responses to painful heat stimuli and their relation to stimulus and sensation variables were analyzed. Twelve healthy subjects served. Sixty phasic stimuli of varying temperatures above and below pain threshold were delivered through a Marstock thermode in 1 session. Heart rate, respiration, and subjective stimulus ratings were recorded simultaneously. Phasic heat stimulation above and below pain threshold induced a tonic increase of the heart rate lasting up to more than 20 sec. High intensity stimulation generated steeper rises and greater mean increase than low intensity stimulation. In general, heart rate responses were more closely related to subjective sensation than to stimulus intensity. However, differential temporal analysis demonstrates that, until about 3 sec after stimulation, the autonomic response is determined solely by stimulus temperature, whereas, after approximately 6 sec, it is related only to subjective judgement. Accordingly, the heart rate responses reflect both a brief nocifensive reflex induced by the sensory component and, subsequently, a longer-lasting response which seems to be related to affective and/or cognitive evaluation. This separation of different stages of pain-processing by an autonomic indicator may be useful in clinical algesimetry.     

Parametric trial-by-trial prediction of pain by easily available physiological measures

Pain is commonly assessed by subjective reports on rating scales. However, in many experimental and clinical settings, an additional, objective indicator of pain is desirable. In order to identify an objective, parametric signature of pain intensity that is predictive at the individual stimulus level across subjects, we recorded skin conductance and pupil diameter responses to heat pain stimuli of different durations and temperatures in 34 healthy subjects. The temporal profiles of trial-wise physiological responses were characterized by component scores obtained from principal component analysis. These component scores were then used as predictors in a linear regression analysis, resulting in accurate pain predictions for individual trials. Using the temporal information encoded in the principal component scores explained the data better than prediction by a single summary statistic (ie, maximum amplitude). These results indicate that perceived pain is best reflected by the temporal dynamics of autonomic responses. Application of the regression model to an independent data set of 20 subjects resulted in a very good prediction of the pain ratings demonstrating the generalizability of the identified temporal pattern. Utilizing the readily available temporal information from skin conductance and pupil diameter responses thus allows parametric prediction of pain in human subjects.     

Brainstem involvement in the initial response to pain

The autonomic responses to acute pain exposure usually habituate rapidly while the subjective ratings of pain remain high for more extended periods of time. Thus, systems involved in the autonomic response to painful stimulation, for example the hypothalamus and the brainstem, would be expected to attenuate the response to pain during prolonged stimulation. This suggestion is in line with the hypothesis that the brainstem is specifically involved in the initial response to pain. To probe this hypothesis, we performed a positron emission tomography (PET) study where we scanned subjects during the first and second minute of a prolonged tonic painful cold stimulation (cold pressor test) and nonpainful cold stimulation. Galvanic skin response (GSR) was recorded during the PET scanning as an index of autonomic sympathetic response. In the main effect of pain, we observed increased activity in the thalamus bilaterally, in the contralateral insula and in the contralateral anterior cingulate cortex but no significant increases in activity in the primary or secondary somatosensory cortex. The autonomic response (GSR) decreased with stimulus duration. Concomitant with the autonomic response, increased activity was observed in brainstem and hypothalamus areas during the initial vs. the late stimulation. This effect was significantly stronger for the painful than for the cold stimulation. Activity in the brainstem showed pain-specific covariation with areas involved in pain processing, indicating an interaction between the brainstem and cortical pain networks. The findings indicate that areas in the brainstem are involved in the initial response to noxious stimulation, which is also characterized by an increased sympathetic response.     

Heart rate mediation of sex differences in pain tolerance in children

Despite evidence supporting the existence of important sex-related differences in pain, the mechanisms underpinning such differences are not well understood. The aim of this study is to examine the relationship between sex and pubertal differences in autonomic arousal and pain tolerance to laboratory pain stimuli in healthy children. We tested the following specific hypotheses: (1) females would have greater autonomic arousal and less pain tolerance than males, and (2) this sex difference in pain tolerance would be mediated by autonomic arousal. Participants were 244 healthy children (50.8% female, mean age 12.73+/-2.98 years, range 8-18 years). Separate 4-trial blocks of cutaneous pressure and thermal pain stimuli were presented in counterbalanced order. Heart rate (HR) was recorded during 2-3 min periods preceding each block and a 1-min period between trials. Results indicated lower tolerance in females for cutaneous pressure, but not thermal pain, compared to males. In addition, pre-trial HR was greater for females than males. Mediation analyses suggested that sex differences in pressure pain tolerance were accounted for by sex differences in pre-trial HR. There were also significant effects for puberty, but these did not vary by sex. Overall, early pubertal children had greater pre-trial HR and less pain tolerance than those in late puberty for both cutaneous pressure and thermal pain across sex. These results suggest that autonomic arousal may be a mediator of sex-related differences in pain responses in children.     

Establishing a link between heart rate and pain in healthy subjects: a gender effect.

Heart rate (HR) is currently used by rehabilitation clinicians as a complementary objective measure of pain. The premise is that, as pain increases, HR should also increase. However, this relationship is not clearly established. The goal of this study was to verify the relationship between HR and pain perception. Thirty-nine healthy volunteers participated in this experimental study. Painful stimuli were induced by a 2-minute immersion of the hand in hot water (47 degrees C). HR was recorded before and during the stimulation and was matched to a pain rating. We observed a rise of 11% in HR after 2 minutes of immersion. There was a significant intrasubject correlation between HR and pain intensity (r = 0.50, P < .001) and pain unpleasantness (r = 0.55, P < .001). Furthermore, there was a strong gender effect in the intersubject correlations. Men presented a strong correlation between mean HR and mean pain perception (intensity: r = 0.77, unpleasantness: r = 0.86), whereas this relationship was absent in women (intensity: r = -0.2, unpleasantness: r = 0.001). In conclusion, results show that, for healthy volunteers, experimental pain can elicit a rise in HR up to 11%. Moreover, the relationship between HR response and pain is gender related. Considering that a positive relationship between HR and pain perception was only found in men, these results do not support a clinical significance of the use of HR for pain evaluation in women. Clinical implications need to be further evaluated with patients before clinicians can use HR as a complementary tool in pain assessment. PERSPECTIVE: A positive correlation between HR and pain was observed for men but not for women. These differences underline the importance of taking into account gender differences in the development of complementary pain assessment. Further research should be conducted to verify the role of sex hormones on heart rate and pain.     

Anticipatory brainstem activity predicts neural processing of pain in humans

Previous neuroimaging studies have shown brain activity during not only the application of noxious stimuli, but also prior to stimulation. The functional significance of the anticipatory response, however, has yet to be explored. Two theoretical responses involve either a decrease or an increase in sensitivity of the nociceptive system. In a functional magnetic resonance imaging (fMRI) study, brainstem responses during anticipation and processing of thermal noxious stimuli were investigated. Twelve healthy subjects were warned prior to and then received noxious stimulation to their left hand. Behavioral data showed a positive correlation between the intensity of anticipation and pain. FMRI data revealed brainstem activation in the PAG during the anticipation period. When correlated with individual anticipation ratings, activation during anticipation included significant clusters within the entorhinal cortex and ventral tegmental area (VTA). During receipt, activation within the brainstem included the PAG, VTA, rostral ventromedial medulla (RVM), and the parabrachial nucleus (PB), all elements of descending pain pathways. Using a backward model approach, we explored the functional significance of the anticipatory neural response for subsequent pain processing. Results of this regression analysis revealed that insula activity during receipt was predicted by activity in both the entorhinal cortex and VTA during anticipation. We suggest that activation in both regions before and during pain may underlie anticipation and subsequent pain modulatory responses, possibly involving the appraisal and control of attention necessary for pain modulation. Together, the results suggest a possible role of brainstem areas in anticipatory mechanisms involved in the maintenance of chronic pain.     

Asians differ from non‐Hispanic Whites in experimental pain sensitivity

This study examined differences between Asians and non‐Hispanic Whites (Whites) in pain sensitivity, and its relationship to mean arterial pressure (MAP) and heart rate (HR). In 30 Whites (50% female) and 30 Asians (50% female), experimental pain sensitivity was assessed with a hand cold pressor task, yielding measures of pain threshold, tolerance, intensity, and unpleasantness. Mean arterial pressure and HR measurements taken at rest and in response to speech stress were assessed. Perceived stress, anxiety, perfectionism, parental criticism, parental expectations and depressive symptoms were also measured. The results indicated that for the cold pain test, Asians demonstrated significantly lower pain threshold and tolerance levels than Whites. Although no ethnic differences were seen for MAP or HR responses to stress, for Whites higher stress MAP levels were correlated with reduced pain sensitivity, while for Asians higher baseline and stress HR levels were correlated with reduced pain sensitivity. Asians reported higher parental expectations and greater parental criticism than Whites. For Asians only, higher levels of perfectionism were related to more depressive symptoms, anxiety and perceived stress. These results indicate that Asian Americans are more sensitive to experimental pain than Whites and suggest ethnic differences in endogenous pain regulatory mechanisms (e.g. MAP and HR). The results may also have implications for understanding ethnic differences in clinical pain.     

Cardiovascular responsiveness to brief cognitive challenges and pain sensitivity in women.

The primary purpose of the study was to determine the relationship between cardiovascular (CV) responsiveness to brief cognitive tasks and pain sensitivity in normotensive individuals. Fifty-eight healthy women without a history of chronic pain were exposed to three laboratory tasks (reading aloud, speech task, and tracking task) and repeated pain testing (electrocutaneous and pressure pain stimulation) while mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Generally, subjects with higher HR responsiveness to the cognitive tasks displayed a reduced pain sensitivity, particularly to electrocutaneous pain stimulation. Moreover, the two types of pain stimulation seemed to trigger somewhat different CV response patterns. Inclusion of pain-related CV changes as control variables affected the relationship between HR responsiveness and pain sensitivity, although differently for electrocutaneous and pressure pain. However, inclusion of psychological control variables had no significant effects. Although relatively large CV changes were observed during the experimental tasks, small and insignificant changes in simultaneous or subsequent electrocutaneous pain sensitivity occurred. However, significant increases in pressure pain threshold and tolerance occurred after the speech task, during which MAP level was at its highest. The present findings support the hypothesis that pain sensitivity and CV response share a common mechanism, which, however, is not necessarily linked to either elevated blood pressure levels or other risk factors for hypertension.     

Sex differences in cardiac and autonomic response to clinical and experimental pain in LBP patients.

Rehabilitation professionals are currently using heart rate (HR) in order to assess the sincerity of effort in certain evaluations. It has been shown that a relation exists between HR and pain but no study has measured cardiac response during both clinical and experimental pain among a patient population using an intra-subject design. Thirty patients with low back pain (LBP) participated in this study including 16 men. Clinical pain was induced by applying a postero-anterior pressure (PA) on a painful lumbar segment for 15 and 30s in order to reproduce the patient's typical LBP at an intensity ranging between 50 and 70/100. Experimental pain was induced with a 15s thermal stimulus at a temperature which reproduced the same pain intensity as the 15s PA. For both reproduced clinical pain durations, we observed a rise in HR ranging between 8.5% and 12.67%. However, unlike men, women's cardiac response failed to show a constant rise in HR during the 30s PA. For all subjects, the rise in HR was much lower during the experimental pain condition (p<0.001), reaching only 5%. On the other hand, galvanic skin responses were significantly higher during the experimental pain condition (p<0.001). During this same condition, women also had a greater rise in galvanic skin responses than men (p=0.04). Finally, a significant correlation was found between both types of pain. These results suggest that pain induced during a clinical evaluation will produce a significant HR augmentation. However, heart rate variability analysis showed greater sympathetic cardiac regulation for men. The sex differences observed in this study call for caution when interpreting HR during pain assessment.     

The effects of auricular transcutaneous electrical nerve stimulation (TENS) on experimental pain threshold and autonomic function in healthy subjects.

The present study examines the effects of auricular transcutaneous electrical nerve stimulation (TENS) on electrical pain threshold measured at the ipsilateral wrist and autonomic functions including skin temperature, blood pressure and pulse rate in 24 healthy subjects. TENS was administered as low frequency trains of pulses delivered at a 'strong but comfortable' intensity to 1 of 3 auricular points to be examined: (i) autonomic effects (autonomic point), (ii) pain threshold effects (wrist point), and (iii) placebo effects at an unrelated point (face point). A fourth untreated group was designated as a situation control. The main finding of the study was that auricular TENS produced no significant overall effects on experimental pain threshold or autonomic functions recorded under the present conditions. However, pain threshold was found to increase by over 50% of its pretreatment baseline in 4 subjects and by 30% in 6 subjects. This rise was not dependent upon the site of auricular TENS. The possible mechanisms of such changes are discussed.     

Health related quality of life and quantitative pain measurement in females with chronic non-malignant pain.

The aim of the present study was to assess, compare, and correlate the pain response to an experimental pain stimulus (hyperalgesia to pressure pain threshold (PPT) measured from different body sites), the pain intensity (VAS) of the habitual pain, and quality of life parameters (SF-36) in groups of females with chronic non-malignant pain syndromes. Forty female pain patients with fibromyalgia/whiplash (n = 10), endometriosis (n = 10), low back pain (n = 10), or rheumatoid arthritis (n = 10), as well as 41 age-matched healthy female controls participated in the study. The fibromyalgia/whiplash patients scored significantly higher (p < 0.04) VAS ratings (median rating = 7.0) than the endometriosis (6.0), low back pain (6.0), and rheumatoid arthritis (3.5) patients. All fours patient groups had significantly lower PPTs at all sites as compared with controls. The fibromyalgia/whiplash patients experienced the highest influence of pain on their overall health status, particularly vitality, social function, emotional problems, and mental health. A significant negative correlation was found between VAS rating and quality of life (p < 0.04). Significant correlation (p < 0.05) was found between pressure hyperalgesia measured at lowest PPT sites and the impairment of SF-36 physical function as well as mental health parameters. This study demonstrates significant generalised pressure hyperalgesia in four groups of chronic pain patients, correlations between degree of pressure hyperalgesia and impairment of some quality of life parameters, and increased pain intensity of the ongoing pain is associated with decreased quality of life.     

Effects of skin-to-skin contact on autonomic pain responses in preterm infants

The purpose of this randomized crossover trial was to determine the effects on autonomic responses in preterm infants of longer Kangaroo Care (30 minutes, KC30) and shorter KC (15 minutes, KC15) before and throughout heel stick compared with incubator care (IC). Beat-to-beat heart rate (HR) and spectral power analysis of heart rate variability, low frequency power (LF), high frequency power (HF), and LF/HF ratio were measured in 26 infants. HR changes from Baseline to Heel Stick were significantly less in KC30 and KC15 than in IC, and more infants had HR decrease in IC than in 2 KC conditions. In IC, LF and HF significantly increased from Baseline to Heel Stick and dropped from Heel Stick to Recovery; in 2 KC conditions, no changes across study phases were found. During Heel Stick, LF and HF were significantly higher in IC than in KC30. In all 3 conditions, LF/HF ratio decreased from Baseline to Heel Stick and increased to Recovery; no differences were found between IC and two KC conditions. Both longer and shorter KC before and throughout heel stick can stabilize HR response in preterm infants, and longer KC significantly affected infants' sympathetic and parasympathetic responses during heel stick compared with incubator care. PERSPECTIVE: This study showed that KC has a significant effect on reducing autonomic pain responses in preterm infants. The findings support that KC is a safe and effective pain intervention in the neonatal intensive care unit.     

Autonomic responses to heat pain: Heart rate, skin conductance, and their relation to verbal ratings and stimulus intensity

In human pain experiments, as well as in clinical settings, subjects are often asked to assess pain using scales (eg, numeric rating scales). Although most subjects have little difficulty in using these tools, some lack the necessary basic cognitive or motor skills (eg, paralyzed patients). Thus, the identification of appropriate nonverbal measures of pain has significant clinical relevance. In this study, we assessed heart rate (HR), skin conductance (SC), and verbal ratings in 39 healthy male subjects during the application of twelve 6-s heat stimuli of different intensities on the subjects’ left forearm. Both HR and SC increased with more intense painful stimulation. However, HR but not SC, significantly correlated with pain ratings at the group level, suggesting that HR may be a better predictor of between-subject differences in pain than is SC. Conversely, changes in SC better predicted variations in ratings within a given individual, suggesting that it is more sensitive to relative changes in perception. The differences in findings derived from between- and within-subject analyses may result from greater within-subject variability in HR. We conclude that at least for male subjects, HR provides a better predictor of pain perception than SC, but that data should be averaged over several stimulus presentations to achieve consistent results. Nevertheless, variability among studies, and the indication that gender of both the subject and experimenter could influence autonomic results, lead us to advise caution in using autonomic or any other surrogate measures to infer pain in individuals who cannot adequately report their perception.     

Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception

The neural mechanisms whereby placebo conditioning leads to placebo analgesia remain unclear. In this study we aimed to identify the brain structures activated during placebo conditioning and subsequent placebo analgesia. We induced placebo analgesia by associating a sham treatment with pain reduction and used fMRI to measure brain activity associated with three stages of the placebo response: before, during and after the sham treatment, while participants anticipated and experienced brief laser pain. In the control session participants were explicitly told that the treatment was inactive. The sham treatment group reported a significant reduction in pain rating (p = 0.012). Anticipatory brain activity was modulated during placebo conditioning in a fronto-cingulate network involving the left dorsolateral prefrontal cortex (DLPFC), medial frontal cortex and the anterior mid-cingulate cortex (aMCC). Identical areas were modulated during anticipation in the placebo analgesia phase with the addition of the orbitofrontal cortex (OFC). However, during altered pain experience only aMCC, post-central gyrus and posterior cingulate demonstrated altered activity. The common frontal cortical areas modulated during anticipation in both the placebo conditioning and placebo analgesia phases have previously been implicated in placebo analgesia. Our results suggest that the main effect of placebo arises from the reduction of anticipation of pain during placebo conditioning that is subsequently maintained during placebo analgesia.     

Potential biobehavioral mechanisms of recurrent abdominal pain in children

To explain why otherwise healthy children experience recurrent episodes of abdominal pain (the recurrent abdominal pain syndrome, or RAP), it has been hypothesized that the child with RAP demonstrates: (1) a deficit in autonomic nervous system recovery to stress, and/or (2) an enhanced behavioral and subjective response to pain. To evaluate the validity of these assumptions, children with RAP (9–14 years) and hospital and healthy controls matched for age, sex, ethnicity and SES were exposed to a cold pressor stimulus (0 ± 1°C). Autonomic (peripheral vasomotor and heart rate), somatic (forearm EMG), subjective (pain intensity and distress), and behavioral (facial expression) responses were recorded during baseline, stressor and recovery periods. At all 4 levels of observation, the cold pressor stimulus resulted in significant autonomic, somatic, subjective and behavioral arousal. However, no significant differential response across the 3 groups was noted for any measure and, in particular, no recovery deficit in autonomic arousal was demonstrated. These findings do not support the assumption of a differential response to an acute laboratory induced stress in children with RAP compared to control children.     

Functional activity mapping of the mesial hemispheric wall during anticipation of pain

The relative contributions of autonomic arousal and of cognitive processing to cortical activity during anticipation of pain, and the role of changes in thalamic outflow, are still largely unknown. To address these issues, we investigated with functional magnetic resonance imaging (fMRI) the activity of the contralateral mesial hemispheric wall in 56 healthy volunteers while they expected the stimulation of one foot, which could be either painful or innocuous. The waiting period was characterized by emotional arousal, a moderate rise in heart rate, and by increases in mean fMRI signals in the medial thalamus, mid- and posterior cingulate cortex, and in the putative foot area of the primary somatosensory and motor cortex. The same brain regions, excepting posterior cingulate, were also activated by somatosensory stimulation. We identified by cross-correlation analysis a cluster population whose fMRI signal time course was related to the mean heart rate (HR) profile, showing selective changes of activity during the waiting period. Positively correlated clusters were found mainly in sensorimotor areas, mid- and posterior cingulate, and dorsomedial prefrontal cortex. Negatively correlated clusters predominated in the perigenual anterior cingulate and ventromedial prefrontal cortex. HR clusters had different characteristics from, and showed limited spatial overlap with, clusters whose fMRI signals were related to the psychophysical pain intensity profile; however, both cluster populations were affected by anticipation. These findings unravel a complex pattern of brain activity during uncertain anticipation of noxious input, likely related both to changes in the level of arousal and to cognitive modulation of the pain system.