A PET activation study of brush-evoked allodynia in... : PAIN (original) (raw)
1. Introduction
Under normal physiological conditions, noxious stimulation activates brainstem areas, contralateral thalamus, primary and secondary somatosensory cortex (SI and SII), insula and the ACC (Casey et al., 1996; Coghill et al., 1999; Svensson et al., 1998). These areas are believed to play an important role in the sensory-discriminative and cognitive aspects of pain processing. Peripheral nerve injury induces hyperexcitability of the peripheral nervous system and spinal cord (LaMotte et al., 1991; Simone et al., 2004) with sensory perception changes and spontaneous pain. Functional brain imaging studies have shown that the default pain-induced brain activation pattern is altered under experimental or clinical hyperalgesic conditions such as capsaicin-induced allodynia (Baron et al., 1999; Iadarola et al., 1998; Witting et al., 2001) and peripheral or central nerve injury pain (Petrovic et al., 1999; Peyron et al., 1998; 2004). We (Witting et al., 2001) and others (Baron et al., 1999; Iadarola et al., 1998) have shown that capsaicin-induced allodynia produces a unique pattern of increased activity in the prefrontal and posterior parietal (BA 5/7) cortex with unaltered activity in primary recipient zones of spinal input such as the thalamus, SI and ACC, suggesting that brain activity patterns not just passively reflect hyperexcitability at peripheral levels.
One would expect that more permanent lesions of the peripheral or central nervous system are likewise associated with a similar altered cerebral response pattern. However, the sparse available data are equivocal, some reports describing a different cerebral activation pattern (Peyron et al., 1998; 2004), others a pattern close to that observed in conditions of normal physiological pain (Hsieh et al., 1995; Petrovic et al., 1999). A possible reason for the discrepancy between the results of studies on experimental and clinical forms of allodynia is that they used different experimental procedures. Another possibility is that clinical allodynia studies used patient populations with heterogeneous pain pathology and lacked detailed quantitative sensory information. The aim of this study was therefore to investigate the cerebral response pattern in a homogeneous group of patients with allodynia following peripheral nerve injury, using identical methodological procedures for evoking allodynia as in our earlier study of capsaicin-induced allodynia. In addition, detailed quantitative sensory testing (QST) was carried out.
Neuropathic pain is an ego-dystonic type of sensation, which is difficult to describe except for the fact that it is very unpleasant and different from any other type of pain that the patient had experienced before. It often consists of a mixture of constant ongoing pain and stimulus-evoked pain (Jensen & Baron, 2003; Jensen et al., 2001). Therefore, we hypothesized that neuropathic pain will recruit brain structures involved in the encoding of coincident sensory input and in emotional processing, such as the ACC and the prefrontal and posterior parietal cortices. Part of this study has been presented in abstract form (Witting et al., 2002).
2. Materials and methods
2.1. Subjects
Nine patients (6 men and 3 women) with an average age of 52 years (range 34–78) participated in the study after given informed verbal and written consent. All participants had long-standing clinical brush-evoked allodynia following upper or lower extremity traumatic nerve injury. The study was approved by the local ethics committee of Aarhus County and was conducted in accordance with the Helsinki II declaration.
2.2. Medical history and clinical examination
A medical history with detailed information on pain was obtained in all patients. Five patients were treated with non-steroidal anti-inflammatory or mild opioid drugs that were stopped at least 12h before sensory examination or scanning. One patient continued with acetylsalicylic acid as a prophylactic antitrombotic agent and two participants were treated with tricyclic antidepressants that were stopped at least one week before examination. Finally, one patient continued with the intake of a selective serotonin reuptake inhibitor, which originally was prescribed because of depressive symptoms.
All participants completed the Danish version of the McGill Pain questionnaire (Drewes et al., 1993). In addition, they rated ongoing and evoked pain on a 100mm visual analogue scale (VAS, 0=no pain, 100=most intense pain).
2.3. Quantitative sensory testing (QST)
The QST was carried out in the area of maximal tolerable brush-evoked allodynia and in the contralateral mirror area. All measurements were done in the same order by the same examiner (NW) in a quiet room at ambient room temperature.
The test stimuli were applied to the same skin area and were not moved between trials because some of the nerve-injured areas were small. Adaptation or sensitization may therefore have influenced the QST results. However, these factors should affect the QST data of all subjects to the same extent. Moreover, the main focus of this study was to investigate the relationship between sensory characteristics and rCBF increases.
2.3.1. Brush-evoked allodynia
Allodynia was evoked by a handheld soft hairbrush that was moved along the skin at a speed of one stroke per 4s, stimulating an area of about 2cm2 (0.5×4cm; brush-velocity of 0.7cm/s, approximate force applied of 0.15–0.20N/cm2). The participants rated the evoked pain continuously on an electronic VAS.
2.3.2. Thermal sensitivity
Heat and cold detection thresholds (HDT, CDT) and heat and cold pain thresholds (HPT, CPT) were determined with a thermotester (Somedic AB, Sweden) using the method of limits. The baseline temperature was set at 30°C and the temperature change rate at 1°C/s. Thresholds were determined as the average of five measurements with 3s interstimulus interval.
2.3.3. Tactile sensitivity
Tactile detection thresholds (TDT) and tactile pain thresholds (TPT) were measured with von Frey filaments (Semmes-Weinstein monofilaments, Stoelting, IL, USA) applied to the skin in ascending order.
2.3.4. Temporal summation
Temporal summation was evoked, as described previously (Gottrup et al., 2003), by repetitively tapping the skin with a von Frey hair (125.9g=1236mN) driven by a computer-controlled solenoid at a rate of 2Hz for 1min or until pain became intolerable. Patients rated evoked pain continuously on an electronic VAS.
2.3.5. Pressure pain
Pressure pain thresholds were measured with a handheld electronic pressure algometer (Somedic AB, Sweden) with a circular 1cm2 probe mounted at the end and a pressure rate of 30kPa/s. The threshold was determined as the average of five measurements. Successive measurements were separated by at least 15s.
2.4. Stimulation procedure and PET and MRI scanning
During the PET examination, subjects were scanned four times in each of the following conditions: (1) rest=ongoing pain, (2) brush on affected skin=brush-evoked allodynia, and (3) brush on homologous contralateral normal skin=brushing of normal skin. Brush began 10s before tracer injection and was continued throughout the acquisition period. Since the majority of patients were suffering from spontaneous pain, the rest condition is different from the rest condition in most studies of experimental pain. The three conditions were performed in a semi-randomized order and the participants were not informed about the sequence of the conditions. The brush paradigm was identical to that used in the QST session. Immediately after each scan, patients rated average pain intensity and pain unpleasantness.
An ECAT Exact HR47 positron emission tomograph (Siemens/CTI 961, Knoxville, TN, USA) scanner was used for data acquisition. The participants were positioned supine in the scanner with the ears plugged and the eyes closed. To limit head movements, the head was restrained in a vacuum pillow. Prior to the emission tomograms, a Ga-68 transmission scan was acquired in 2D mode for attenuation correction. Emission tomograms were obtained in 3D mode after bolus injection of 500MBq (5ml) H215O. The 60s data acquisition frame started automatically at 60,000 true counts. PET images were reconstructed and filtered to 12mm spatial resolution (FWHM) (Hann filter: cut-off frequency=0.15 cycles/pixel). For anatomical coregistration, a T1-weighted MRI was acquired on a GE Sigma 1 Tesla scanner, providing slices of 1.5mm thickness. A nine-parameter affine transformation was used to normalize each brain to the Talairach coordinate system (Talairach & Tournoux, 1988). The MINC-TRACC algorithm (Collins et al., 1994) or automated image coregistration software system (AIR) (Woods et al., 1992) were used for MRI–PET and PET–PET coregistration to correct for motion artifacts. All coregistrations were visually checked for goodness of fit. One patient was unable to go through the MRI procedure due to claustrophobia. The PET data from this patient were coregistered to the average MRI of the other participants. In patient number 6 the last three PET scans could not be carried out because of intolerable pain. The data from this participant were analyzed as described for the other subjects.
2.5. Statistical analysis
2.5.1. Pain during PET
A paired t-test was carried out to compare VAS scores of ongoing pain with those of allodynia. The level of significance was set at _P_≤0.05.
2.5.2. PET data
Voxel counts were normalized to the global cerebral blood flow. Statistical evaluation of voxel-by-voxel subtractions was based on _t_-statistic with the assumption of zero mean and a standard deviation pooled over the image volume. For activation sites in gray matter (500ml), not expected a priori, a significance level of _t_=4.3 (P(0.05) was adopted (Worsley et al., 1992). This model corrects for multiple comparisons and furthermore adjusts for the fact that activity in adjacent voxels is highly intercorrelated and therefore not independent. Using a cut-off _t_-value of 4.3 will yield less than 0.05 false positive in the search volume. The statistical software used was glim_image developed at the Montreal Neurological Institute. A priori activation was expected in the thalamus, striatum, SI, SII, ACC, insula, parietal cortex BA 5/7, cerebellum, prefrontal cortex and mesencephalon (Iadarola et al., 1998). For these areas, _t_-values corresponding to a P value ≤0.05 were determined according to the corresponding volume of the area (Worsley, 1996). The volume of an area was calculated from the results of published PET pain activation studies (Witting et al., 2001) as a sphere with a diameter corresponding to the most extreme coordinates reported. This is suggested to be a conservative estimate because of the discrepancies in the literature on the outer limits of an area (Aziz et al., 1997; Coghill et al., 1999; Derbyshire & Jones, 1998; Hsieh et al., 1996; May et al., 1998b; Peyron et al., 1998).
Data from patients with right-sided pain were mirrored and analyzed together with data from patients with left-sided pain (entire group). Main effects were calculated for the contrasts ‘allodynia vs. rest’ and ‘brushing vs. rest’. To compare for significant rCBF differences between allodynic brushing and brushing on the contralateral side, a post hoc comparison was performed, using the activations from the main contrasts (‘ brush–rest’ and ‘allodynia–rest’ ) as masks. Thereto, measures of allodynia-evoked rCBF increases were calculated in the regions defined by the main contrasts (see Table 2). The same was done in the homologous side of the left hemisphere to calculate for brush-evoked rCBF increases. Thereafter, a direct comparison was made between the allodynia (right hemisphere) -and brush-evoked (left hemisphere) rCBF increases, using a paired _t_-test. A level of _P_≤0.05 was considered as statistically significant. Finally, single subject analyses were also carried out.
PET results (group analyses)
3. Results
3.1. Clinical characteristics
Table 1 summarizes the clinical observations. All patients had peripheral nerve injury pain lasting from 6 months to several years (130±48 months). The nerve injury was caused by trauma (_N_=5), amputation (_N_=2) or operation (_N_=2).
Patient characteristics
3.2. Quantitative sensory testing
3.2.1. Ongoing pain and allodynia
Seven participants reported ongoing pain with an average VAS score of 32±10mm. All patients reported brush-evoked allodynia with an average VAS score of 61±8mm. Fig. 1 shows the location of allodynia on body maps. Seven patients described their allodynia by word descriptors from the MPQ category as ‘ burning’. Two subjects had amputations of one or two fingers but they did not show signs of phantom limb pain during the QST examination.
Anatomical distribution of the area of brush-evoked allodynia for each of the nine patients indicated in gray shading.
3.2.2. Thermal sensitivity
Examination of cold and heat detection and pain thresholds showed that all patients had abnormal thermal sensitivity with ≥2°C threshold differences between the normal and affected side. Five patients had elevated heat and three had elevated cold detection thresholds. Four patients indicated decreased heat pain thresholds and another four decreased cold pain thresholds. Two patients reported increased heat pain thresholds and two increased cold pain thresholds.
3.2.3. Tactile sensitivity
All patients had abnormal tactile sensation (≥2 von Frey hair filaments difference between thresholds on affected and non-affected side). Three patients had increased and one decreased detection thresholds, whereas two reported increased and six decreased pain thresholds.
3.2.4. Temporal summation and pressure pain
All patients had hyperalgesia to pressure stimuli (decreased pressure pain thresholds) and increased temporal summation.
3.3. PET results
During PET scanning, the average ongoing VAS pain score at rest was 37±10mm. When brushing the affected skin area, brush-evoked pain intensity -and unpleasantness were resp. 59±10mm and 64±9mm. The average brush-evoked allodynia was 60±8 (paired _t_-test: P<0.001 compared to resting pain). The values are very close to those obtained in the preceding QST session, further underscoring the validity of our measures.
3.3.1. Allodynia-evoked and brush-evoked rCBF changes (compared to rest)
Brush-evoked allodynia selectively induced a significant rCBF increase in contralateral orbitofrontal (BA 11) cortex, ipsilateral insula and cerebellum (Table 2 and Fig. 2). In contrast, only brushing of normal skin induced significant rCBF increases in contralateral SI and posterior parietal (BA 5) cortex (Table 2 and Fig. 2).
Brush-evoked (A) and allodynia-evoked (B) rCBF changes. Normal brush (right body side) produced rCBF changes in contralateral SI and BA5/7 (slice 60), bilateral SII (slice 25) and contralateral insula (slice 10). Allodynic brushing (left body side) produced a highly significant rCBF increase in contralateral orbitofrontal cortex, ipsilateral cerebellum (slice -20), ipsilateral insula (slice 10) and bilateral SII but with preponderance of ipsilateral activation (slice 25). Coordinates below refer to the location of peak voxels in _z_-space. Brains are displayed in neurological convention (left, left side of the brain).
3.3.2. Post hoc direct comparison of allodynia-evoked and brush-evoked rCBF increases
Allodynia was associated with significantly stronger rCBF increases in ipsilateral anterior insula, prefrontal cortex (BA 11) and cerebellum. In contrast, normal brush was associated with significantly stronger rCBF increases in SI and BA 5 (Fig. 3)
Post hoc comparison ‘allodynia–brush’ using the activations from the main contrasts as masks. The figure shows percentage of rCBF increases following allodynic and normal brushing. A direct comparison between the allodynia-evoked and brush-evoked rCBF increases revealed that allodynia was associated with significantly higher rCBF increases in the ipsilateral anterior insula, prefrontal cortex (BA11) and cerebellum. In contrast, normal brushing was associated with significantly stronger rCBF increase in SI and BA5.
3.3.3. Single subject analyses
All subjects showed significant allodynia-induced rCBF increases in prefrontal cortex and SII/insular area. Five patients also showed an rCBF increase in thalamus. A higher interindividual variability in the rCBF response was observed in SI, ACC and BA 5/7 (Table 3).
PET results at single subject level during allodynia as compared to rest (_t_>2.5)
4. Discussion
The main finding of this study is that brush-evoked allodynia in patients suffering from peripheral nerve injury pain activates the contralateral orbitofrontal and ipsilateral anterior insular cortex. These data are in contrast with those observed in acute nociceptive pain. They also differ from results of experimental brush-evoked allodynia following capsaicin administration, which activates prefrontal, insular, SII and posterior parietal (BA 5/7) cortices (Baron et al., 1999; Iadarola et al., 1998; Witting et al., 2001).
4.1. Methodological concerns
We incorporated several control conditions in our study design such as stimulation of the contralateral non-affected limb and a detailed QST examination of the patients prior to study inclusion. The QST data provide evidence that all patients suffered nerve injury as indicated by sensory abnormalities in the affected skin area. Notwithstanding, a number of methodological concerns remain. First, the study was carried out in a relatively small number of patients of both sexes involving both right and left upper and lower limb nerve injuries. Accordingly, we cannot rule out the possibility that some of the negative findings, as for example the lack of SI and BA 5/7 activations, might be due to interindividual differences in pain somatotopy. However, the fact that these areas were activated by brushing of the non-affected skin and that robust activations were observed in other cortical regions argues against this hypothesis. Moreover BA 5/7 activation was also reported in a small group of patients suffering from pain in different anatomical locations (Petrovic et al., 1999).
4.2. Orbitofrontal cortex (BA 11)
The orbitofrontal cortex (BA 11) was selectively activated during brush-evoked allodynia. Although two previous studies of clinical brush-evoked allodynia did not mention prefrontal activation (Petrovic et al., 1999; Peyron et al., 2004), several studies of experimental allodynia and other pathological pain states or conditions with tissue injury reported prefrontal activation (Baron et al., 1999; Hsieh et al., 1995; 1996; Iadarola et al., 1998; Kupers et al., 2000; 2004; Lorenz et al., 2002; May et al., 1998a; Peyron et al., 1998; Rosen et al., 1994; Wiech et al., 2005; Witting et al., 2001). In rats, orbitofrontal neurons respond to noxious stimulation (Dostrovsky et al., 1995; Yang et al., 1998) and nerve injury-induced allodynia and hyperalgesia are blocked by administration of morphine or lidocaine in orbitofrontal cortex (Al-Amin et al., 2004; Baliki et al., 2003). The prefrontal cortex has widespread reciprocal connections with cortical and subcortical sensory processing areas (Fuster, 1997) and electrical stimulation of orbitofrontal cortex in the cat inhibits areas in the mesencephalon and reduces noxious-evoked spinal reflexes (Dostrovsky et al., 1995). Combined anatomical, neurophysiological and lesion studies indicate that the orbitofrontal cortex may be important in drive inhibition and regulation of internal and external sensory and motor stimuli (Fuster, 1997). The prefrontal cortex may therefore participate in the adaptive responses to pain, which may include descending pain modulation. The fact that the prefrontal cortex sends strong projections to the periaqueductal grey, a key structure in the descending modulation of pain, further underscores this hypothesis (An et al., 1998). Previous brain imaging studies already demonstrated that the orbitofrontal cortex exerts a pain modulatory effect in acute experimental pain (Petrovic et al., 2002; Valet et al., 2004). The present data add new evidence for a more general role of this area in the endogenous modulation of pain.
An alternative explanation for the orbitofrontal activation relates to the role of this area in the monitoring and decoding of externally applied stimulation. In their comprehensive review, Kringelbach & Rolls (2004) postulate an anterior-posterior specification of functions whereby simple stimuli, e.g. a noxious stimulus, are decoded in posterior orbitofrontal areas whereas more complex stimuli such as multisensory or unpleasant stimuli tend to be encoded more anteriorly. Our orbitofrontal activation site is about midway between these two poles, which may be explained by the multisensory input or the unpleasantness of the allodynic stimulation. The recent report that orbitofrontal activity correlates with subjective pain intensity (Wiech et al., 2005) further underscores this hypothesis.
Functional brain imaging studies have also shown that expectation of pain and anticipatory anxiety may activate the orbitofrontal cortex (Hsieh et al., 1999; Simpson et al., 2001). It might therefore be argued that expectation or anticipatory anxiety for pain are the basis of our orbitofrontal activation. Since, we started sensory stimulation 10s before the PET data acquisition, it is unlikely that our orbitofrontal activation was mediated by anticipation or anxiety.
4.3. Insular cortex and enhanced ipsilateral responses
In line with results of previous studies on clinical neuropathic (Peyron et al., 1998; 2004; Petrovic et al., 1999) and capsaicin-induced allodynia (Iadarola et al., 1998; Witting et al., 2001), we observed a strong activation in the insular/SII area during allodynic brushing. In man, the insula is one of the most consistently activated brain areas in response to painful stimulation (Frot & Mauguiere, 2003; Peyron et al., 2000; 2002) and electrical stimulation of the insula through implanted electrodes produces painful or unpleasant sensations (Ostrowsky et al., 2002). Some of the insular neurons responding to noxious stimulation are somatosensory convergent and also respond to light brush stimulation (Zhang et al., 1999). These neurons may be activated by the combination of ongoing pain and brush-evoked allodynia. The fact that we also observed an insular response during brushing of normal skin, where normal brush stimulation coexists with ongoing pain, gives further support to this hypothesis.
It is worth mentioning that the allodynia-induced insular activation was particularly strong in the hemisphere ipsilateral to stimulation. An abnormally elevated ipsilateral activation in the insular/SII region was also reported in response to cold -and brush-evoked allodynia in a large series of neuropathic pain patients (Peyron et al., 2004). It is unclear whether this plastic response participates in the changed perception from non-painful to allodynic sensation.
4.4. Absence of expected rCBF changes
4.4.1. SI, ACC and thalamus
In spite of robust activations in orbitofrontal cortex, insula and cerebellum, other components of the pain matrix such as SI, ACC and thalamus did not show significant rCBF increases following allodynic stimulation. Although negative findings should be interpreted cautiously, methodological factors, such as the inclusion of patients with pain at various locations or stimulus characteristics could explain this lack of activation. Alternatively, it may be hypothesized that the absence of SI, thalamic and ACC activation is causally related to the pain following nerve injury. Earlier studies reported a shift in the cortical representation of SI in patients with phantom limb pain (Flor et al., 1998; Peyron et al., 1998). The present data show a strong SI activation during normal brushing, but not during allodynic brushing. We speculate that the absence of SI activity is pathophysiologically linked to allodynia.
A priori, we expected activation of ACC because of the known unpleasant character of allodynic stimulation. Anterior cingulated activation has been demonstrated in response to ongoing pain and allodynia following nerve injury (Hsieh et al., 1995; Petrovic et al., 1999; Peyron et al., 2000; 2004). Since most of our patients were also suffering from ongoing pain, a possible explanation might be that the ACC was already active in the baseline state and that allodynia was unable to further increase the elevated levels of ACC activity. In line with this hypothesis, the single subject analyses showed that three of the four subjects with ACC activation had no or relatively low levels of ongoing pain.
4.4.2. Superior posterior parietal cortex (BA 5/7)
In marked contrast with our previous study on capsaicin-induced brush-evoked allodynia (Witting et al., 2001), clinical allodynia was not associated with a significant activation of the superior posterior parietal cortex (BA 5/7).
A possible explanation, documented by the QST data, is that differentiation might have lead to a reduced stimulus-induced activation in BA 5/7. Two previous studies did report BA 5/7 activation following clinical brush-evoked allodynia (Petrovic et al., 1999) or pin-prick hyperalgesia (Maihofner et al., 2005), but we have no QST data from these patients.
4.5. Mechanisms of central sensitization
Following nerve injury, loss of sensory input may lead to a reduction of inhibitory input from afferent fiber systems thereby creating a state of central sensitization. The reduced thalamic and SI activity in the present study may be related to decreased lemniscal input with a subsequent development of disinhibition-induced hyperexcitability. The sensory information may follow alternative ascending pathways to reach the brain. One such pathway is the spinoreticulothalamic tract, which has been suggested to mediate hyperalgesia (Garcia Larrea et al., 2002). Another candidate is the newly described pathway relaying nociceptive specific information from the parabrachial internal lateral neurons via the paracentral thalamic nucleus and to the prefrontal cortex (Bourgeais et al., 2001). In addition, mechanical allodynia may be an ‘interactive phenomena’ in which supraspinal centers, such as the rostral ventral medulla (Burgess et al., 2002), exert abnormal modulation of dorsal horn neurons (Burgess et al., 2002; Bian et al., 1998; Kauppila et al., 1998).
The present finding of orbitofrontal and preferential ipsilateral SII and insular activation coexisting with absence of activation in SI, ACC and thalamus may reflect these anatomical and functional changes.
Acknowledgements
The study was supported by grants from the Danish Medical Research Council (no. 9502209), the Svend Andersen Foundation (to R.K.) Karen Elise Jensen's Foundation and Institute for Experimental Clinical Research, Aarhus University, Denmark.
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Keywords:
Allodynia; Neuropathic pain; Sensory testing; Functional brain imaging; Reorganization; Orbitofrontal cortex
© 2006 Lippincott Williams & Wilkins, Inc.