Brain Advance Access originally published online on September 2, 2006
Brain 2006 129(11):2957-2965; doi:10.1093/brain/awl228
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pain sensitivity and fMRI pain-related brain activity in Alzheimer's disease
1 Howard Florey Institute, University of Melbourne Parkville, Victoria, Australia 2 Centre for Neuroscience, University of Melbourne Parkville, Victoria, Australia 3 Department of Mathematics and Statistics, University of Melbourne Parkville, Victoria, Australia 4 Department of Medicine, University of Melbourne, University of Melbourne Parkville, Victoria, Australia 5 National Ageing Research Institute Parkville, Victoria, Australia
Correspondence to: Leonie J. Cole, Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australia E-mail: l.cole{at}hfi.unimelb.edu.au
 |
Summary |
|---|
 Top Summary IntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
|---|
People with Alzheimer's disease are administered fewer analgesics and report less clinical pain than cognitively intact peers with similar painful diseases or injuries, prompting speculation about the likely impact of neurodegeneration on central pain processing. The present study measured pain ratings and functional MRI (fMRI) brain responses following mechanical pressure simulation in 14 patients with Alzheimer's disease and 15 age-matched controls. Contrary to the prevailing hypothesis that this disease is likely to differentially reduce emotional responses to pain, we show that activity in both medial and lateral pain pathways is preserved. Moderate pain was evoked with similar stimuli in both groups, and was associated with a common network of pain-related activity incorporating cingulate, insula and somatosensory cortices. Between-group analyses showed no evidence of diminished pain-related activity in Alzheimer's disease patients compared with controls. In fact, compared with controls, patients showed greater amplitude and duration of pain-related activity in sensory, affective and cognitive processing regions consistent with sustained attention to the noxious stimulus. The results of this study show that pain perception and processing are not diminished in Alzheimer's disease, thereby raising concerns about the current inadequate treatment of pain in this highly dependent and vulnerable patient group.
Key Words: Alzheimer's disease; pain; fMRI; aged
Abbreviations: aMCC, anterior midcingulate cortex; BA, Brodmann area; BOLD, blood oxygen level-dependent; DLPFC, dorsolateral prefrontal cortex; fMRI, functional magnetic resonance imaging; IC, insula cortex; JNP, just noticeable pain; M1, primary motor cortex; MMSE, Mini-Mental State Examination; MP, moderate pain; ROI, region of interest; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; WP, weak pain
Received March 24, 2006. Revised July 17, 2006. Accepted July 25, 2006.
|
Introduction |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
|---|
Patients with Alzheimer's disease have been shown to receive fewer analgesics and report less clinical pain than cognitively intact peers with similar levels of painful disease or injury (Farrell et al., 1996
; Cook et al., 1999; Frampton, 2003). Compared with healthy age-matched controls, patients have also shown higher tolerances to experimental pain (Benedetti et al., 1999). It remains unclear whether the observed difference in pain report and management occurs as a result of impaired communication and memory of pain, and/or whether the perception and experience of pain is altered as a result of the progressive degeneration of cortical and subcortical regions involved in the transmission and processing of nociceptive information (Farrell et al., 1996; Scherder et al., 2003, 2005).
Pain is a complex and subjective perceptual experience, incorporating sensory-discriminative, affective-motivational and cognitive-evaluative dimensions (Melzack and Casey, 1968). These aspects of the pain experience are subserved by distinct supraspinal pathways. The lateral pain system consists of spinothalamic tract neurons that ascend via the ventroposterior lateral thalamus onto the primary and secondary somatosensory cortices (S1 and S2) which in turn code the location, intensity, and quality of the sensation. Another major pathway branches at the level of the medulla and ascends via the medial thalamus to hypothalamic nuclei, limbic regions including the cingulate cortex, the insula cortex (IC) and onto prefrontal areas, all of which are known to be involved in the control of emotion, arousal and attention. This medial pain pathway is proposed to mediate the unpleasant, affective dimensions of pain, and the motivation to escape from the noxious event (Treede et al., 1999; Price, 2000).
Converging lines of evidence from brain imaging (Thompson et al., 2003) and patho-histological (Braak and Braak, 1997; Nagy et al., 1997; Rub et al., 2002) research suggest the neurodegenerative changes that occur in Alzheimer's disease selectively target components of the medial pain system, in particular the medial thalamic nuclei, the hypothalamus, cingulate and IC. On the other hand, the cerebral regions comprising the lateral pain pathway are relatively well preserved, suggesting that the disease may compromise the affective-motivational component of pain more so than the sensory-intensity dimension (Scherder and Bouma, 1997; Scherder, 2000). Moreover, a disorder of cognition such as Alzheimer's disease, in which deficits in memory and reasoning are cardinal symptoms, would be expected to have a profound effect on an individual's appraisal of the pain experience and its future implications.
While there is a strong theoretical rationale to expect altered pain transmission and processing in patients with Alzheimer's disease, there has been limited empirical research to address this issue in terms of functional consequences, and studies to date have yielded mixed results with regard to the magnitude and direction of any change in pain perception that occurs in this illness. A dissociation between sensory-discriminative and affective-motivational aspects of pain has been suggested by reports that subjects show comparable thresholds for pain detection, but increased tolerance to strong pain when compared with intact controls (Benedetti et al., 1999), as well as blunted autonomic responses to impending pain (Porter et al., 1996; Rainero et al., 2000; Benedetti et al., 2004). Others have also suggested that the perception of acute pain is preserved, while the experience of chronic pain may be altered (Pickering et al., 2006). In contrast to these reports, Gibson et al. (2001) showed that CNS activation, as indexed by the peak amplitude of pain-related event potentials is not diminished in Alzheimer's disease, although a delayed latency to peak response in the patient group suggests the transmission and integration of nociceptive input may be slower in these patients (Gibson et al., 2001). While this study provides some information about the cortical processing of noxious information in Alzheimer's disease, the lack of spatial resolution afforded by EEG measures limits the conclusions that can be drawn regarding the extent to which pain-related CNS processing may be altered by the disease. Finally, a disturbance of the cognitive aspects of the pain experience was recently demonstrated by Benedetti et al. (2006), who found that expectation-related pain relief after open analgesic administration was reduced in patients compared with controls.
In the present study, we compared pain sensitivity and supraspinal processing of nociceptive input in patients with Alzheimer's disease and cognitively intact controls. Psychophysical measurements were collected to investigate the dissociation between sensory and affective-motivational aspects of pain. A response-dependent method was used to determine the amount of mechanical pressure required to elicit three levels of sensation: just noticeable pain (JNP), weak pain (WP) and moderate pain (MP). Ratings of unpleasantness in response to stimuli delivered at each of these threshold levels were also collected.
In order to test the assertion that reduced pain report occurs as a result of selective damage to medial thalamic and limbic structures involved in affective-motivational pain processing, functional magnetic resonance imaging (fMRI) measures of CNS pain processing were collected. Research using fMRI has been able to dissociate medial and lateral pain system functioning, thereby demonstrating cerebral activity associated with sensory and emotional pain perception (Ingvar, 1999; Peyron et al., 2000; Bornhovd et al., 2002). To date, no studies have used this method to examine altered CNS pain processing in persons with Alzheimer's disease. Using a group-by-region approach to fMRI data analysis, we aimed to directly compare pain-induced blood oxygenation-level-dependent (BOLD) activity in regions of interest (ROIs) located in medial and lateral pain pathways. We hypothesized that selective impairment of affective-motivational pain processing would be evidenced by significantly less pain-related activity in medial pain-pathway regions in patients compared with controls, coupled with comparable between-group pain-related activity in lateral pain-pathway regions. Given that there have been no previous studies of CNS pain processing on patients with Alzheimer's disease, haemodynamic response properties were also explored in other regions showing between-group differences in pain-related activity.
|
Material and methods |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
|---|
Participants
Sixteen verbally communicative patients with Alzheimer's disease were recruited from the Melbourne Health Cognitive and Dementia Memory Service in Parkville, Australia. Patients were examined by a trained neurologist, gerontologist and psychogeriatrician, and diagnosed according to the criteria specified by the ICD-10, DSM-IV and NINCDS–ADRDA. Cognitive functioning was further assessed using the Mini-Mental State Examination (MMSE) (Folstein et al., 1975
). A study control group of 16 age- and sex-matched cognitively intact individuals were recruited from a volunteer registry held at the National Aging Research Institute in Parkville, Australia. Two patients who were unable to provide reliable pain ratings, and one control subject whose MRI scan revealed a brainstem lesion were excused from the study. Thus a total of 14 patients (7 males; mean age = 79 ± 5 years; mean MMSE score = 19.4 ± 5.7) and 15 age-matched healthy control volunteers (9 males; mean age = 79 ± 4 years; mean MMSE score = 29.3 ± 0.1) completed the study. All subjects reported no pre-existing pain and were not taking any analgesic medications at the time of testing. Conditions that could potentially alter pain sensitivity, including peripheral neuropathy, diabetes, stroke, hypertension and psychiatric disorders, also served as exclusion criteria. Informed consent was gained from all participants, and in the case of patients, third-party consent was also given by the treating physician and the next of kin. The study protocol was approved by the Human Research Ethics Committees of the Howard Florey Institute, Melbourne Health, and St Vincent's Hospital as well as the Guardianship Board (VCAT).
Procedures
The study was conducted over two sessions. In an initial psychophysical testing session, mechanical pressure stimuli of 5 s in duration were applied to the thumbnail of the right hand in a triple random staircase procedure to determine thresholds for just noticeable pain (JNP), weak pain (WP) and moderate pain (MP). Pressure stimuli were delivered via a 1 cm2 circular rubber probe attached to a hydraulically-driven piston which transmits forces generated by calibrated weights in increments of 0.25 kg/cm2 (Gracely et al., 2004). Participants rated the intensity of each stimulus trial using a combined numerical and descriptor box scale ranging from 0 to 20 where 0 = no pain sensation, 0.5 = JNP, 5 = WP and 11 = MP (Petzke et al., 2005). Participants were asked to rate the intensity of each stimulus trial immediately after stimulus removal. The subjective rating of pain was used to determine the magnitude of the next stimulus delivered in the respective staircase. To avoid sensitization of the thumbnail, stimuli were delivered at least 20 s apart. In a subsequent session, anatomical and fMRI data were collected on a 1.5 T Siemens Symphony MR scanner located at St Vincent's Hospital, Melbourne, Australia. Anatomical images were acquired in the axial orientation (108 slices, 2 mm slice thickness, 0.94 x 0.94 mm2 resolution, TE = 3.08 ms, TR = 1620 ms). Echo planar images were also acquired in the axial plane (36 slices, 4 mm slice thickness, 3.5 x 3.5 mm2 resolution, TE = 40 ms; TR = 3000 ms, FA = 90°) as participants were exposed to three levels of pressure stimulation (innocuous pressure, WP, and MP) at the intensity levels determined during the previous psychophysical test session. Pressure stimuli were pseudo-randomly presented in 30 s blocks interspaced with 24 s no-stimulus periods over three functional scans. At the end of each scan participants were asked to rate the pain at its most intense. On the basis of these ratings, the stimulus intensity delivered in subsequent runs was adjusted if necessary.
Statistical analysis
fMRI data from individual subjects were pre-processed (realigned to correct for subject movement and scanner drift, normalized to a standard EPI template and smoothed with a 4 mm FWHM Gaussian kernel) and then statistically analysed with FEAT (FMRI Expert Analysis Tool) Version 5.4, in FSL (FMRIB's Software Library, www.fmrib.ox.ac.uk/fsl) (Smith et al., 2004). Higher-level (group) analyses were carried out using FLAME (FMRIB's Local Analysis of Mixed Effects). Contrasts were performed to identify regions showing increased activity during moderately painful compared with innocuous pressure stimulation. Z (Gaussianized T/F) statistic images were thresholded using clusters determined by Z > 2.3 and a (corrected) cluster significance threshold of P < 0.05. Haemodynamic response properties were also examined using time courses extracted from ROIs in medial and lateral pain pathways. The first medial pathway ROI was located in the anterior midcingulate cortex (aMCC). This region of the cingulate cortex [corresponding with Brodmann area (BA) 24] represents the terminal point of the majority of nociceptive inputs from the medial intralaminar thalamic nuclei (Vogt, 2005), and is consistently activated in studies of functional brain imaging of pain (Farrell et al., 2005; Vogt, 2005). ROIs were also generated for the anterior, mid and posterior subregions of the IC. The lateral pain-pathway ROIs were defined in S1 and S2. We also examined ROIs from the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) to further investigate our unexpected finding of increased pain-related activity in the patient group. ROI volumes contained all activated voxels situated within the selected region, as defined by the Brodmann map supplied with MRIcro (Rorden and Brett, 2000). A combined group activation map, derived by combining data from all subjects, was used to define ROIs so that data from each subject group contributed equally to region definition (Buckner et al., 2000). ROIs were transformed to each subject's own native space and BOLD signal response time courses extracted for each run in individual subjects. These time courses were then averaged across subjects in each group, and repeated-measures ANOVAs (with Greenhouse–Geisser corrections for non-sphericity) were conducted to examine between-group differences in the temporal characteristics of the haemodynamic response during and after moderately painful stimulation.
|
Results |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
|---|
Psychophysical results
Pain sensitivity thresholds following mechanical pressure stimulation were determined for the group of patients and the age-matched cognitively intact control group (Fig. 1A). The capacity of subjects to provide consistent ratings of noxious and innocuous stimuli during psychophysical procedures was evaluated by summing the number of stimuli required to resolve each random staircase. Analysis of variance of stimuli number showed no effect for group membership [F(1,27) = 2.1, n.s.], a significant effect of threshold level [F(1,27) = 6.0, P < 0.05], and the absence of any interaction between group and threshold level [F(1,27) = 1.1, n.s.]. Post hoc testing with paired t-tests established that the mean number of stimuli required to resolve thresholds for JNP and WP were greater than the mean number for MP. The mean stimulus intensities required to elicit reports of JNP, WP and MP were higher for the patient group compared with controls [F(1,27) = 5.79, P < 0.05]. However, contrary to a previous report (Benedetti et al., 1999
), the difference was most significant at the level of JNP. Patients did not provide lower ratings for pain unpleasantness as would be predicted by a reduction in medial pain pathway functioning. In fact they gave higher unpleasantness ratings for pain threshold stimuli compared with controls (Fig. 1B).
|
Functional magnetic resonance imaging results
Analysis of fMRI data revealed a common network of pain-related activity, with both groups showing increased activity in both the medial and lateral pain systems during noxious versus innocuous pressure stimulation (Table 1; Fig. 2). This included increased activity in the aMCC, IC, medial thalamus, S1 and S2. Between-group analyses failed to reveal any evidence of greater pain-related activity in the control group compared with the patient group. However, compared with controls, patients showed significantly greater pain-related activity in several pain-pathway regions, including the aMCC (Talairach co-ordinates: 2, 8, 32) and (0, 10, 46), ventrolateral and dorsomedial thalamus (–10, –10, 12) and (6, –18, 12), S1 (–58, –14, 42), posterior parietal cortex (–4, 12, 68) and frontal regions including the DLPFC (40, 12, 56) and (–22, 36, 46). In addition, several motor pathway regions, including M1 (42, –16, 62) and (–54, –8, 42), supplementary motor area (SMA; –4, 12, 68) and cerebellum (–4, –68, –28) showed greater pain-evoked responses in the Alzheimer's disease group compared with controls (Fig. 3; Supplementary Table 1).
|
|
|
Haemodynamic response properties in selected regions of interest
Haemodynamic response properties were examined in ROIs from the medial pain pathway (aMCC and anterior, mid and posterior subregions of the contralateral IC) and lateral pain pathway (S1 and S2). Time courses of BOLD signal activity from the aMCC and left anterior IC (aIC) reveal between-group similarities in mean percentage signal change amplitude and in the latency to peak response (Fig. 4A and B). However, differences in temporal characteristics of the haemodynamic response can be observed, most notably in the slower return to baseline after moderately painful stimulation in the Alzheimer's disease group. Repeated-measures ANOVAs confirmed significant between-group differences in BOLD signal intensity change over time in the aMCC [F(5,126) = 3.52, P < 0.01] and aIC [F(7,180) = 1.80, P < 0.05]. The patient group also showed a perseveration of BOLD signal activity relative to controls in the mid IC [F(8,215) = 2.08, P < 0.05], which did not differ significantly from the pattern observed in the aIC [F(8,213) = 1.13, n.s.]. The temporal profiles of BOLD signal change in the posterior insula did not significantly differ between groups [F(8,211) = 1.07, n.s.], with neither group showing sustained activity beyond stimulus removal. Time courses from lateral pain pathway ROIs show that peak response amplitude was greater and had a slower latency in the patient group compared with controls. As seen in medial pathway ROIs, the increase in BOLD signal is also more prolonged for the patient group in S1 [F(5,143) = 4.36, P < 0.005] and S2 [F(6,168) = 4.06, P < 0.005] (Fig. 4C and D).
|
To further explore between-group differences in pain-related activation, BOLD signal time courses were plotted in two prefrontal regions (left and right DLPFC) and two motor regions (left and right M1) (Fig. 5). The patient group showed greater peak response amplitude compared to controls in both left and right DLPFC (Fig. 5A and B). There was also significant perseveration of response in the patient group in left DLPFC [F(6,148) = 2.54, P < 0.05]. However, in the right DLPFC, the temporal characteristics of the haemodynamic response did not differ significantly between groups [F(4,106) = 2.29, n.s.]. Response amplitudes did not differ between groups in the left M1; however, the activation was more prolonged in the patient group compared with controls [F(6,154) = 2.28, P < 0.05] (Fig. 5C). Finally, BOLD signal time courses from the right M1 show significantly increased BOLD signal in the patient group during moderately painful stimulation, with an absence of response from controls (Fig. 5D).
|
In order to check whether the between-group differences in BOLD signal change observed with noxious stimulation reflect differences in central pain processing, and not simply an overall slowing of the haemodynamic response, the temporal characteristics of BOLD responses during innocuous pressure were also analysed. The perseveration of BOLD signal activity in patients relative to controls observed with MP stimulation was not in evidence during innocuous pressure stimulation. Repeated-measures analysis of variance revealed no significant between-group difference in the BOLD signal response following innocuous pressure stimulation [F(1,26) = 0.406, n.s.], and there were no significant interactions between group x time [F(7,172) = .57, n.s.] nor group x time x region [F(14,364) = 0.94, n.s.].
|
Discussion |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
|---|
There has been much speculation concerning the nature of pain perception in Alzheimer's disease, and the potential disease-related changes to the CNS transmission and processing of nociceptive information that may occur (Scherder et al., 2005
). This study is the first to directly investigate these issues using both psychophysical and fMRI measures of responses to pain.
Our finding of higher thresholds for pain sensitivity in Alzheimer's disease patients compared with control subjects is in partial agreement with previous reports (Benedetti et al., 1999; Rainero et al., 2000). However, ratings given for the unpleasantness of painful stimuli delivered at comparable perceptual intensities were not significantly lower in patients compared with controls. The elevated JNP threshold in the patient group was accompanied by elevated unpleasant ratings compared with the healthy controls. The most parsimonious explanation for this outcome is that the patients adopted a more stringent internal benchmark for what constituted JNP. Preliminary instructions to subjects emphasized the need to draw a distinction between the experience of innocuous pressure, and just detectable degrees of pain. Memory impairment could diminish the efficacy of preliminary instructions in the patient group, possibly resulting in a tendency to dismiss very low levels of pain as inconsequential. Unpleasantness ratings of frankly painful levels of stimulus in the patient group would consequently exceed the rating of near-threshold levels of pain in the control group.
Functional brain imaging data produced no evidence of reduced pain-related activity in medial pain regions in patients compared with healthy controls, indicating that the affective/emotional aspects of the pain experience are not selectively diminished in these patients, in contrast to the previously hypothesized view (Scherder and Bouma, 1997; Scherder et al., 2003, 2005). In fact, compared with controls, the Alzheimer's disease group showed perseveration of pain-related activity across all components of the pain network, including the aMCC and a/mIC.
While our data provide no evidence for diminished emotional responsiveness to moderately painful stimulation in patients, prolonged activation in the pain pathway along with increased activity in cognitive processing regions such as the DLPFC indicate that the cognitive integration of the painful experience may be altered. Attenuation of BOLD signal responses, with signal decay occurring prior to the removal of a noxious stimulus, has previously been reported in studies of the temporal dynamics of the pain-evoked brain activation (Kurata et al., 2002; Ibinson et al., 2004). This observed decay in BOLD signal following noxious input can be explained in terms of diminished attention to a painful stimulus (Peyron et al., 1999; Brooks et al., 2002). Engagement in attention-demanding cognitive tasks has also been shown to decrease pain-related activity in several components of the pain network, including S1, S2 and IC (Seminowicz et al., 2004). Alternatively, it may be argued that the decay in haemodynamic response with pain observed in the control subjects may reflect habituation to the stimulus. However, previous psychophysical evaluations of responses elicited by the same stimulus modality have reported no evidence of habituation. The stimulus has been shown to produce replicable sensations (Gracely et al., 2002, 2004), and serial pain intensity ratings have been previously found to slightly increase over 30 s stimulus trials, suggesting that subjects are more likely to sensitize than habituate to the stimulus (unpublished observations). Moreover, it is unlikely that patients and controls differentially habituated to the stimulus, given that the number of stimulus trials required to determine pain thresholds did not significantly differ between groups. Thus, the perseveration of pain-related brain activity observed in patients compared with controls more likely reflects sustained attention to the stimulus, rather than impaired habituation.
Pain demands attention by its very nature. However, in situations where the threat of tissue damage is low, such as the experimental pain environment, the propensity to escape from the stimulus is necessarily suppressed. Under such circumstances, it is more adaptive to disengage attention from the experience of pain. In the present study, the attenuation in pain-evoked activity in the older control group of subjects can be interpreted as an accurate appraisal of pain in an experimental setting, and consequent disengagement of attention from the sensation. On the other hand, the perseveration of the initial pain response seen in the Alzheimer's disease group may be modulated by ongoing attention to the stimulus, due to an impaired capacity to integrate novel and recent somatosensory experiences with contextual information. Compared with controls, the patient group also had greater pain-related activity across the motor network, including M1, premotor cortex, SMA and cerebellum. This increase in motor activity suggests inadequate inhibition of withdrawal responses, and provides further evidence of impaired cognitive integration of the pain experience.
Further evidence of an altered cognitive response to pain is provided by the increased DLPFC activity in this group of patients. The DLPFC is known to be involved in working memory processing and attention (Barch et al., 1997; Mesulam, 1998; Smith and Jonides, 1999; MacDonald et al., 2000). Previous research has shown increased prefrontal activity in Alzheimer's disease patients compared with controls during the performance of cognitive tasks (Grady et al., 2003; Pariente et al., 2005a; Starr et al., 2005). The increase in prefrontal activity has been found to correlate with improved memory performance (Remy et al., 2005) and may reflect heightened attentional engagement in difficult tasks (Pariente et al., 2005a). Recent evidence from pain imaging research suggests that the DLPFC may also play a role in the cognitive modulation of pain (Bornhovd et al., 2002; Lorenz et al., 2002, 2003; Brighina et al., 2004; Gracely et al., 2004; Graff-Guerrero et al., 2005; Pariente et al., 2005b; Zubieta et al., 2005). For instance, Lorenz et al. (2002) found increased DLPFC activity during the stimulation of chemically-sensitized skin with a normally innocuous thermal stimulus (heat allodynia) compared with stimulation of non-sensitized skin with a noxious thermal stimulus (heat pain), even though the perceived intensity of the stimuli was the same for both conditions. The authors note that increased activity in the DLPFC is usually seen in pain studies involving real or perceived tissue pathology, such as allodynia, abdominal pain or neuropathic pain. Given that the future implications of pathological pain states differ to those of normal experimental pain conditions, increased DLPFC activity may reflect altered emotional and cognitive responses to potentially harmful noxious stimulation. Following this line of reasoning, the increased DLPFC activity in Alzheimer's disease group compared with cognitively intact controls in the present study may indicate an increased threat value of the pain for the patients, on account of their impaired ability to appropriately appraise the likely consequences of the experimental pain stimulus. This is consistent with a recent report of altered expectations of pain-relief in patients (Benedetti et al., 2006). First and foremost, Alzheimer's disease is a disorder of cognition, and consequently it is not surprising that the disease is likely to impact on the cognitive domain of the pain experience.
It is important to note that while our cohort of patients all had a clinical diagnosis of Alzheimer's disease, they were still in the early stages of disease progression, with the group mean MMSE score (19.4 ± 5.7) indicating a mild-to-moderate degree of cognitive impairment. It is possible that the nature of pain perception may differ between cases with mild Alzheimer's disease and those with more advanced stages. Thus, the difference between our psychophysical results and those previously reported may be related to differences in the level of cognitive impairment of the respective samples. However, given that the disease follows a predicted course, with medial thalamic nuclei and medial temporal structures such as the cingulate cortex among the first regions to become degraded (Rub et al., 2002; Thompson et al., 2003), any reduction in the cognitive-emotional aspects of the pain experience would be expected to manifest in the early stages of the disease.
Overall, the pattern of pain-related brain activity observed with fMRI suggests that the central processing of nociceptive information is not diminished in Alzheimer's disease patients. In fact, the experience of pain may be more distressing for these patients on account of their impaired ability to accurately appraise the unpleasant sensation and its future implications. The results of the present study therefore have significant clinical implications, and raise important concerns about the current inadequate treatment of pain in this highly dependent and vulnerable group.
|
Supplementary material |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
|---|
Supplementary data are available at Brain Online.
|
Acknowledgements |
|---|
This study was supported by NH&MRC grant (219291). We thank all the participants, care givers and clinicians involved in the study, in particular David Ames from St George's Hospital for his help with the assessment and recruitment of patients. We also gratefully acknowledge the contributions of Nicolas Trost and Mark Lorenz from the MR department at St Vincent's Hospital, Melbourne.
|
References |
|---|
|
TopSummaryIntroductionMaterial and methodsResultsDiscussionSupplementary materialReferences |
|---|
Brach DM, Braver TS, Nystrom LE, Forman SD, Noll DC, Cohen JD. (1997) Dissociating working memory from task difficulty in human prefrontal cortex. Neuropsychologia 35:1373–80.[CrossRef][Web of Science][Medline]
Benedetti F, Vighetti S, Ricco C, Lagna E, Bergamasco B, Pinessi L, et al. (1999) Pain threshold and tolerance in Alzheimer's disease. Pain 80:377–82.[CrossRef][Web of Science][Medline]
Benedetti F, Arduino C, Vighetti S, Asteggiano G, Tarenzi L, Rainero I. (2004) Pain reactivity in Alzheimer patients with different degrees of cognitive impairment and brain electrical activity deterioration. Pain 111:22–9.[CrossRef][Web of Science][Medline]
Benedetti F, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I, et al. (2006) Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective. Pain 121:133–44.[CrossRef][Web of Science][Medline]
Bornhovd K, Quante M, Glauche V, Bromm B, Weiller C, Buchel C. (2002) Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study. Brain 125:1326–36.
Braak H and Braak E. (1997) Staging of Alzheimer-related cortical destruction. Int Psychogeriatr 9:Suppl. 1, 257–61 discussion 269–72.[Medline]
Brighina F, Piazza A, Vitello G, Aloisio A, Palermo A, Daniele O, et al. (2004) rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. J Neurol Sci 227:67–71.[CrossRef][Web of Science][Medline]
Brooks JC, Nurmikko TJ, Bimson WE, Singh KD, Roberts N. (2002) fMRI of thermal pain: effects of stimulus laterality and attention. Neuroimage 15:293–301.[CrossRef][Web of Science][Medline]
Buckner RL, Snyder AZ, Sanders AL, Raichle ME, Morris JC. (2000) Functional brain imaging of young, nondemented, and demented older adults. J Cogn Neurosci 12:Suppl. 2, 24–34.
Cook AK, Niven CA, Downs MG. (1999) Assessing the pain of people with cognitive impairment. Int J Geriatr Psychiatry 14:421–5.[CrossRef][Web of Science][Medline]
Evans AC, Marrett S, Neelin P, Collins L, Worsley K, Dai W, et al. (1992) Anatomical mapping of functional activation in stereotactic coordinate space. Neuroimage 1:43–53.[Medline]
Farrell MJ, Katz B, Helme RD. (1996) The impact of dementia on the pain experience. Pain 67:7–15.[CrossRef][Web of Science][Medline]
Farrell MJ, Petzke F, Grant MAB, Clauw DJ, Gracely RH. (2000) Continuous and fluctuating pressure stimuli provoke pain of equivalent intensity and disparate unpleasantness. 19th Annual Meeting, American Pain Society pp. 147.
Farrell MJ, Laird AR, Egan GF. (2005) Brain activity associated with painfully hot stimuli applied to the upper limb: a meta-analysis. Hum Brain Mapp 25:129–39.[CrossRef][Web of Science][Medline]
Folstein MF, Folstein SE, McHugh PR. (1975) ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–98.[CrossRef][Web of Science][Medline]
Frampton M. (2003) Experience assessment and management of pain in people with dementia. Age Ageing 32:248–51.
Gibson SJ, Voukelatos X, Ames D, Flicker L, Helme RD. (2001) An examination of pain perception and cerebral event-related potentials following carbon dioxide laser stimulation in patients with Alzheimer's disease and age-matched control volunteers. Pain Res Manag 6:126–32.[Medline]
Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, et al. (2004) Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain 127:835–43.
Grady CL, McIntosh AR, Beig S, Keightley ML, Burian H, Black SE. (2003) Evidence from functional neuroimaging of a compensatory prefrontal network in Alzheimer's disease. J Neurosci 23:986–93.
Graff-Guerrero A, Gonzalez-Olvera J, Fresan A, Gomez-Martin D, Mendez-Nunez JC, Pellicer F. (2005) Repetitive transcranial magnetic stimulation of dorsolateral prefrontal cortex increases tolerance to human experimental pain. Brain Res Cogn Brain Res 25:153–60.[CrossRef][Medline]
Ibinson JW, Small RH, Algaze A, Roberts CJ, Clark DL, Schmalbrock P. (2004) Functional magnetic resonance imaging studies of pain: an investigation of signal decay during and across sessions. Anesthesiology 101:960–9.[CrossRef][Web of Science][Medline]
Ingvar M. (1999) Pain and functional imaging. Philos Trans R Soc Lond B Biol Sci 354:1347–58.
Kurata J, Thulborn KR, Gyulai FE, Firestone LL. (2002) Early decay of pain-related cerebral activation in functional magnetic resonance imaging: comparison with visual and motor tasks. Anesthesiology 96:35–44.[CrossRef][Web of Science][Medline]
Lorenz J, Cross D, Minoshima S, Morrow T, Paulson P, Casey K. (2002) A unique representation of heat allodynia in the human brain. Neuron 35:383–93.[CrossRef][Web of Science][Medline]
Lorenz J, Minoshima S, Casey KL. (2003) Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 126:1079–91.
MacDonald AW III, Cohen JD, Stenger VA, Carter CS. (2000) Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science 288:1835–8.
Melzack R and Casey K. (1968) Sensory, motivational, and central control determinants of pain. In Kenshalo D and Thomas CC (Eds.). The skin senses.(Springfield, Illinois) pp. 423–43.
Mesulam MM. (1998) From sensation to cognition. Brain 121:1013–52.
Nagy Z, Vatter-Bittner B, Braak H, Braak E, Yilmazer DM, Schultz C, et al. (1997) Staging of Alzheimer-type pathology: an interrater-intrarater study. Dement Geriatr Cogn Disord 8:248–51.[Web of Science][Medline]
Pariente J, Cole S, Henson R, Clare L, Kennedy A, Rossor M, et al. (2005a) Alzheimer's patients engage an alternative network during a memory task. Ann Neurol 58:870–9.[CrossRef][Web of Science][Medline]
Pariente J, White P, Frackowiak RS, Lewith G. (2005b) Expectancy and belief modulate the neuronal substrates of pain treated by acupuncture. Neuroimage 25:1161–7.[CrossRef][Web of Science][Medline]
Petzke F, Harris RE, Williams DA, Clauw DJ, Gracely RH. (2005) Differences in unpleasantness induced by experimental pressure pain between patients with fibromyalgia and healthy controls. Eur J Pain 9:325–35.[CrossRef][Web of Science][Medline]
Peyron R, Garcia-Larrea L, Gregoire MC, Costes N, Convers P, Lavenne F, et al. (1999) Haemodynamic brain responses to acute pain in humans: sensory and attentional networks. Brain 122:1765–80.
Peyron R, Laurent B, Garcia-Larrea L. (2000) Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 30:263–88.[Web of Science][Medline]
Pickering G, Jourdan D, Dubray C. (2006) Acute versus chronic pain treatment in Alzheimer's disease. Eur J Pain 10:379–84.[CrossRef][Web of Science][Medline]
Porter FL, Malhotra KM, Wolf CM, Morris JC, Miller JP, Smith MC. (1996) Dementia and response to pain in the elderly. Pain 68:413–21.[CrossRef][Web of Science][Medline]
Price DD. (2000) Psychological and neural mechanisms of the affective dimension of pain. Science 288:1769–72.
Rainero I, Vighetti S, Bergamasco B, Pinessi L, Benedetti F. (2000) Autonomic responses and pain perception in Alzheimer's disease. Eur J Pain 4:267–74.[CrossRef][Web of Science][Medline]
Remy F, Mirrashed F, Campbell B, Richter W. (2005) Verbal episodic memory impairment in Alzheimer's disease: a combined structural and functional MRI study. Neuroimage 25:253–66.[CrossRef][Web of Science][Medline]
Rorden C and Brett M. (2000) Stereotaxic display of brain lesions. Behav Neurol 12:191–200.[Web of Science][Medline]
Rub U, Del Tredici K, Del Turco D, Braak H. (2002) The intralaminar nuclei assigned to the medial pain system and other components of this system are early and progressively affected by the Alzheimer's disease-related cytoskeletal pathology. J Chem Neuroanat 23:279–90.[CrossRef][Web of Science][Medline]
Scherder E, Oosterman J, Swaab D, Herr K, Ooms M, Ribbe M, et al. (2005) Recent developments in pain in dementia. BMJ 330:461–4.
Scherder EJ. (2000) Low use of analgesics in Alzheimer's disease: possible mechanisms. Psychiatry 63:1–12.[Web of Science][Medline]
Scherder EJ and Bouma A. (1997) Is decreased use of analgesics in Alzheimer disease due to a change in the affective component of pain? Alzheimer Dis Assoc Disord 11:171–4.[Web of Science][Medline]
Scherder EJ, Sergeant JA, Swaab DF. (2003) Pain processing in dementia and its relation to neuropathology. Lancet Neurol 2:677–86.[CrossRef][Web of Science][Medline]
Seminowicz DA, Mikulis DJ, Davis KD. (2004) Cognitive modulation of pain-related brain responses depends on behavioral strategy. Pain 112:48–58.[CrossRef][Web of Science][Medline]
Smith EE and Jonides J. (1999) Storage and executive processes in the frontal lobes. Science 283:1657–61.
Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al. (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23:Suppl 1, S208–19.
Starr JM, Loeffler B, Abousleiman Y, Simonotto E, Marshall I, Goddard N, et al. (2005) Episodic and semantic memory tasks activate different brain regions in Alzheimer disease. Neurology 65:266–9.
Thompson PM, Hayashi KM, de Zubicaray G, Janke AL, Rose SE, Semple J, et al. (2003) Dynamics of gray matter loss in Alzheimer's disease. J Neurosci 23:994–1005.
Treede RD, Kenshalo DR, Gracely RH, Jones AK. (1999) The cortical representation of pain. Pain 79:105–11.[CrossRef][Web of Science][Medline]
Vogt BA. (2005) Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci 6:533–44.[Web of Science][Medline]
Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, et al. (2005) Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 25:7754–62.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. F. Karp, J. W. Shega, N. E. Morone, and D. K. Weiner Advances in understanding the mechanisms and management of persistent pain in older adults Br. J. Anaesth., July 1, 2008; 101(1): 111 - 120. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||