Experimental cranial pain elicited by capsaicin: a PET study

Pain 74 (1998) 61–66

Experimental cranial pain elicited by capsaicin: a PET study A. May a,b,*, H. Kaube a, C. Bu¨chel b, C. Eichten a, M. Rijntjes c, M. Ju¨ptner a, C. Weiller c, H.C. Diener a b

a Department of Neurology, University of Essen, Hufelandstr. 55, 45122 Essen, Germany Wellcome Department of Cognitive Neurology, Institute of Neurology, Queen Square, London WC1N 3BG, UK c Department of Neurology, University of Jena, Philosophenweg 3, 07740 Jena, Germany

Received 8 July 1997; revised version received 30 August 1997; accepted 4 September 1997

Abstract Using a positron emission tomography (PET) study it was shown recently that in migraine without aura certain areas in the brain stem were activated during the headache state, but not in the headache free interval. It was suggested that this brain stem activation is inherent to the migraine attack itself and represents the so called ‘migraine generator’. To test this hypothesis we performed an experimental pain study in seven healthy volunteers, using the same positioning in the PET scanner as in the migraine patients. A small amount of capsaicin was administered subcutaneously in the right forehead to evoke a burning painful sensation in the first division of the trigeminal nerve. Increases of regional cerebral blood flow (rCBF) were found bilaterally in the insula, in the anterior cingulate cortex, the cavernous sinus and the cerebellum. Using the same stereotactic space limits as in the above mentioned migraine study no brain stem activation was found in the acute pain state compared to the pain free state. The increase of activation in the region of the cavernous sinus however, suggests that this structure is more likely to be involved in trigeminal transmitted pain as such, rather than in a specific type of headache as was suggested for cluster headache.  1998 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Positron emission tomography; Brain stem; Regional cerebral blood flow; Experimental pain; Capsaicin; Cavernous sinus

1. Introduction Previous regional cerebral blood flow (rCBF) studies have emphasised a dysfunction of the cerebrovascular regulation in headache while little study has been conducted to evaluate the central processing of headache (Russel and Fanciullacci, 1993). Only recently a study in migraine without aura using positron emission tomography (PET) has shown activation of certain brain stem areas during the spontaneous right-sided acute migraine attack but not in the headache free interval (Weiller et al., 1995). Moreover it was shown that this slightly lateralised brain stem activation was still demonstrable after the injection of 6 mg sumatriptan s.c. had completely relieved the patients from pain and concomitant symptoms. It was therefore concluded that

* Corresponding author. Tel.: +44 171 8373611, ext. 4262; fax: +44 171 8130349; e-mail: [email protected]

the visualised brain stem activation is involved in the genesis of the migraine attack itself, rather than simply being a reaction to trigeminal pain. To further test this hypothesis we conducted an experimental pain study in seven healthy volunteers, using the same positioning in the PET scanner as was used for the migraine patients, focusing our interest on the brain stem. As craniovascular pain is transmitted predominantly through the ophthalmic division of the trigeminal nerve, the other divisions being involved to a lesser extent (Mc Naughton, 1966), a small amount of capsaicin was administered subcutaneously to the forehead to evoke a painful sensation in the first division of the trigeminal nerve. The right side of the volunteer’s head was chosen, as in the previous migraine study only patients with right-sided headache were analysed. We used this approach to detect brain regions with increased blood flow during experimental pain using PET to measure rCBF as an index of regional neuronal activity (Raichle, 1987).

0304-3959/98/$19.00  1998 International Association for the Study of Pain. Published by Elsevier Science B.V. PII S0304-3959 (97 )0 0144-9

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2. Methods 2.1. Volunteers Seven healthy male volunteers (25–35 years old, mean age 30 years) were studied during an acute pain state evoked by injecting a small amount of capsaicin s.c. into the forehead. In all volunteers capsaicin was administered on the right side of the forehead. All seven volunteers had no history of headaches. The participants were all right-handed and free from cerebrovascular and space-occupying intracerebral disease as well as major affective disorders. The study was approved by the ethics committee of the University Hospital of Essen and all participants signed an informed consent. 2.2. Design All volunteers were scanned either five (five volunteers) or six times (two volunteers) prior to the injection. The interscan interval was about 11–12 min (five half-lives of the radionucleide). A minute amount of capsaicin (0.05 ml of a sterile 0.1% solution) was then injected subcutaneously into the right forehead, about 2 cm above the eyebrow and immediately before each activation scan. Pain was described as being analogous to a bee-sting and reached the maximum intensity immediately following injection. The pain and autonomic symptoms (tearing and slight rhinorrhoe) remained for the entire duration of each scan (i.e., 1–2 min). During the acute pain state five or six scans were again performed. The eyes were closed during all scans and volunteers were told not to move during the scans.

chosen because of a strong regional a priori hypothesis based on the clinical and experimental data cited in the text. As it is impossible to properly randomise the design of the study (i.e., no pain – pain – no pain – pain) due to the nature of the stimulus used, one criticism might be that effects seen are simply time effects. To address this issue, an additional analysis was performed, using time over 10 respectively 12 observations, as a covariate of no interest.

3. Results 3.1. Increased rCBF during pain During the acute pain state compared to the resting state increases in rCBF were found bilaterally in the anterior insula (BA 13), the contralateral thalamus, the ipsilateral anterior cingulate cortex (BA 24/32) and in the cerebellum bilaterally. In addition there was a bilateral activation pattern in midline structures over several planes (from −32 mm to −20 mm with respect to the anterior cingulate-posterior cingulate line (ac-pc line), slightly lateralised to the left, anteriorly to the brain stem and posteriorly to the chiasma region with the focus of maximum significance located at +2, +2, −22 mm in Talairach co-ordinates (Fig. 1). Superimposed on an MRI template, the location of the activation most likely covers intracranial arteries as well as the region of the cavernous sinus bilaterally, but more marked on the ipsilateral side. This holds true in the group study, as well as in five out of seven single subject studies (Fig. 2). The results are presented in Table 1. 3.2. Decreased rCBF during pain

2.3. Data acquisition and analysis rCBF was measured during 10–12 consecutive scans with an integrated H15 2 O slow bolus technique and an ECAT 953–15 PET scanner (CTI, Knoxville, TN). Five or six runs were performed at rest and again the same number of scans during the acute pain state. After attenuation correction (measured by a transmission scan) the data were reconstructed as 15 transaxial planes by filtered back projection with a Hanning filter with cut-off frequency of 2.5 cycles per cm. The integrated counts accumulated were used as an index of rCBF (Fox and Mintun, 1989). The images were realigned to each other, filtered, transformed into the stereotactic space of Talairach and Tournoux (1988) and normalised for global blood flow differences with analysis of covariance (ANCOVA) (Friston et al., 1995a). Statistical significance was tested using the general linear model –statistical parametric mapping (SPM 96) with the software of the Wellcome Department of Cognitive Neurology, London (http://www.fil.ion.ucl.ac.uk/spm). Rest and pain states were compared voxel by voxel using the t-statistic (Friston et al., 1991, 1995b). Volunteers were analysed individually and in groups. The threshold of P , 0.001 was

Decreased rCBF was found in the fusiform gyrus (BA 37), the cerebellum and the lower parts of the cingulate gyrus (BA 32). The results are presented in Table 2. Using time over 10 respectively 12 observations, as a covariate of no interest, a similar pattern as in the original analysis was demonstrated with less degrees of freedom and therefore slightly decreased significance (data not shown).

4. Discussion PET may represent the best currently available technique for assessing in vivo changes in rCBF in humans. PET scanning allows the detection of subtle changes in rCBF during defined behavioural tasks and provides an index of synaptic activity relating the network of regions to the tested brain function (Frackowiak and Friston, 1994). Recent functional brain imaging studies with PET suggest the involvement of brain stem structures in migraine (Weiller et al., 1995). We used the same technique and the same positioning in the PET scanner that was used for the migraine

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patients with PET. We did so to investigate central processing of experimental cranial pain in the ophthalmic division of the trigeminal nerve in seven healthy volunteers subjected to the subcutaneous injection of a minute amount of capsaicin. The chemogenic algesic agent capsaicin is the pungent ingredient of red peppers which selectively acts on C-fibres. It was chosen for the rapid short-lasting pain

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sensation, while avoiding possible tactile components of the pain stimulus. 4.1. Anterior cingulate cortex Activation of the anterior cingulate cortex (ACC) has repeatedly been reported in PET studies on sensation of

Fig. 1. Comparison of capsaicin induced trigeminal transmitted pain and rest (no pain) condition in seven healthy volunteers. The activations during the pain condition are shown as statistical parametric maps which show the areas of significant rCBF increases (P , 0.001) in colour superimposed on an anatomical reference derived from a T1-weighted MR image. The right side of the picture is the right side of the brain. Significant activation was detected in the cingulate cortex (BA 24/32), bilaterally in the anterior insulae (BA 13) and in the thalamus contralateral to the pain side. The activation seen in the right frontal area is probably due the smoothing effect (10 mm) and represents local hyperemia covering the injection site. BA, Brodmann’s area. Fig. 2. Comparison of capsaicin induced trigeminal transmitted pain and rest (no pain) condition in seven healthy volunteers. The activations during the pain condition are shown as statistical parametric maps which show the areas of significant rCBF increases (P , 0.001) in colour superimposed on an anatomical reference derived from a T1-weighted MR image. The numbers refer to the relative distance to the ACPC-line (joining the anterior and posterior comissures), which is situated at 0 mm. The anterior part of the brain corresponds to the top of the image, the posterior parts to the bottom. The right side of the picture is the right side of the brain. Significant activation was detected over several planes, outside the brain tissue in the region of several intracranial vessels as well as in the region of the cavernous sinus. The activation was bilateral, but more pronounced on the right side, ipsilateral to the head-pain.

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Table 1 Significant increased blood flow during the acute pain state compared with the pain free state Region

Brodmann’s area

Talairach co-ordinates (mm)

Cerebellum

Right insula Cingulate gyrus Left insula Thalamus Cavernous sinus

BA 13 BA 24/32 BA 13

x

y

z

−36 2 24 36 8 −36 −4 2

−82 −92 −90 12 36 6 −2 2

−32 −30 −32 −4 10 2 0 −22

Z score of peak activation

P

5.39 4.70 4.59 4.88 3.80 3.52 2.87 2.44

,0.05* ,0.05* ,0.05* ,0.05* ,0.01 ,0.01 ,0.01 ,0.01

The contrasts are tabulated in terms of the activated brain region and their Brodmann’s areas (BAs), the x, y, z co-ordinates, according to the atlas of Talairach and Tournoux (1988), of each peak (defined as the pixel with the highest Z-score within each activated region). *Corrected for multiple comparison (Friston et al., 1995b).

somatic or visceral pain and attributed to the emotional response to pain (Jones et al., 1992; Casey et al., 1994; Rosen et al., 1994; Hsieh et al., 1996a). While the activation of the ACC in this study was lateralised to the right side, it is noteworthy that in the previous study in right-sided migraine attacks (Weiller et al., 1995) the activation of the ACC was bilaterally extended (BA 24/32) but the maximal activation was also located on the right ACC. This might be due to the strictly lateralised trigeminal input (nociception) with ipsilateral activation in the ACC. One explanation for the fact that previous functional brain imaging studies on experimentally induced pain have demonstrated a contralateralised activation of the BA 24 with acute phasic heat (Mesulam and Mufson, 1985; Jones et al., 1991; Coghill et al., 1994) may be in the quality of pain or in different processing of trigeminal as opposed to body related pain. However, it was suggested that ACC activation, at least in aversive pain, might be unrelated to the side of the initial event and might also be more clustered in the non-dominant hemisphere (Hsieh et al., 1995). 4.2. Anterior insula Increases of rCBF in the insula (BA 13) have been demonstrated in previous studies following application of heat (Casey et al., 1994; Coghill et al., 1994; Minoshima et al., 1995), subcutaneous injection of ethanol (Hsieh et al.,

1996b), somatosensory stimulation (Burton et al., 1993), as well as during cluster headache (Hsieh et al., 1996a) and atypical facial pain (Derbyshire et al., 1994). Given its anatomical connections, the insula has been suggested as a relay of sensory information into the limbic system and is known to play an important role in the regulation of autonomic response (Mesulam and Mufson, 1985). Painful stimuli are significantly effective in activating the anterior insula, a region heavily linked with both somatosensory and limbic systems. Such connections may provide one route through which nociceptive input may be integrated with memory in order to allow a full appreciation of the meaning and dangers of painful stimuli. 4.3. Thalamus The thalamus is one site where changes in rCBF would most be expected in the acute pain state. Activation of the contralateral thalamus due to pain is known from experimental animals (Dostrovsky et al., 1991; Goadsby et al., 1991; Kuroda et al., 1995) as well as functional imaging studies in man (Casey et al., 1994; Rosen et al., 1994; Hsieh et al., 1996b). However, some functional imaging studies did not observe any activation in the thalamus or even a decrease in rCBF (Di Piero et al., 1991; Hsieh et al., 1995). The mechanism underlying the differences may be in the modalities of the employed painful stimuli. The tha-

Table 2 Significant decreased blood flow during the acute pain state compared with the pain free state Region

Fusiform gyrus Cerebellum Cingulate gyrus

Brodmann’s area

BA 37 BA 32

Talairach co-ordinates (mm) x

y

z

−44 46 −8

−48 −42 38

−12 −20 −8

Z score of peak deactivation

P*

6.47 5.62 5.12

,0.05 ,0.05 ,0.05

The contrasts are tabulated in terms of the deactivated brain region and their Brodmann’s areas (BAs), the x, y, z co-ordinates, according to the atlas of Talairach and Tournoux (1988), of each peak (defined as the pixel with the highest Z-score within each deactivated region). *Corrected for multiple comparison (Friston et al., 1995b).

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lamus seems to be more preferentially activated in the pain imaging studies using acute phasic pain stimuli, especially heat pain (Apkarian et al., 1992). 4.4. Cerebellum The acute pain following injection of capsaicin into the right forehead induced an increased rCBF bilaterally in the cerebellum. There appears to be no direct nociceptive input to the cerebellum (Ekerot et al., 1991) and there is no clinical evidence that cerebellar lesions or stimulation affect pain sensation in humans (Casey et al., 1994). However, there are some PET studies which report an activation in this area during experimental pain (Casey et al., 1994; Hsieh et al., 1995, 1996b). 4.5. Brain stem With respect to the above mentioned PET study in nine migraneurs, no brain stem activity was found during the acute pain state compared to the resting state. The brain stem activation in migraine without aura persisted after the injection of Sumatriptan had induced complete relief from headache and concomitant symptoms, such as phono- and photophobia. There was no brain stem activation in the headache free interval (Weiller et al., 1995). Dysfunction in the regulation of brain stem nuclei, which are involved in anti-nociception and extra- and intracerebral vascular control provides a far reaching explanation for many of the facets of migraine (Lance, 1990). It was concluded that the observed activation in the brain stem is not a consequence of pain, but might be the first direct visualisation of the postulated ‘migraine generator’ in man (Weiller et al., 1995). Considering our findings of a lack of brain stem activation in experimental pain, it seems unlikely that the brain stem activation in migraine without aura is simply related to the transmission of pain or due to increased activity of a non-specific antinociceptive system. These findings rather support the idea that the pathogenesis of migraine is related to an imbalance of activity between brain stem nuclei regulating antinociception and vascular control (Goadsby et al., 1991). 4.6. Region of the cavernous sinus The bilateral activation in the region of the cavernous sinus might be an indication of increased venous inflow from the superior ophthalmic vein draining the ophthalmic artery or of a longer transit time for the tracer in this region possibly due to an impeded venous drainage. Another possibility is that the observed increase in activation might be due to a bilateral dilation of the internal carotid artery. It is difficult to assess the contribution of these two possibilities to the measured activity. Using PET, significant activity in the region of the cavernous sinus was previously described in cluster patients (Hsieh et al., 1996a). An inflammatory

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process in the cavernous sinus and tributary veins is discussed as being primarily responsible for cluster headaches (Hardebo, 1994). The inflammation is thought to obliterate the venous outflow from the cavernous sinus on one side, thus injuring the through-running sympathetic fibres of the intracranial internal carotid artery and its branches. The active period ends when the inflammation is suppressed and the sympathetic fibres partially or fully recover (Hardebo, 1994). This theory is based substantially on abnormal findings using orbital phlebography in cluster headache patients (Hannerz et al., 1987a, 1991; Sjaastad, 1992). However, in a study on cluster patients using MRI no definite pathological changes were found in the area of the cavernous sinus (Sjaastad and Rinck, 1990), and using SPECT parasellar hyperactivity was present in 50–80% of cluster patients but in not less than 70% of migraneurs (Sianard-Gainko et al., 1994). What adds to the point that vasodilation and/or inflamation in the cavernous region is not specific for cluster headache is the fact that the same condition was found in patients with Tolosa Hunt syndrome (Hannerz et al., 1986), hemicrania continua (Antonaci, 1994), SUNCT syndrome (Hannerz et al., 1992; Kruszewski, 1992) and chronic paroxysmal hemicrania (Hannerz et al., 1987b; Antonaci, 1994). The frequency of pathologic findings with orbital phlebography in cluster headache was not higher than in cervicogenic headache, migraine and tension-type headache, and the pattern of the pathology was generally the same (Bovim et al., 1992). Considering these facts, our data raise the possibility that vasodilation and/or increase in flow in the cavernous region is not specific for cluster headache or does not form a significant part of the pathophysiology of the acute attack of cluster headache. Our data suggest that activation of the trigeminal system as such triggers the impeded arterial or venous drainage/increase in flow in the region of these vessels.

Acknowledgements The authors wish to thank the participants of this study who patiently endured the painful procedure, Peter Goadsby for fruitful discussions, Andrea Ebersberger for providing the capsaicin solution, Ba¨rbel Terschu¨ren for technical assistance during the scanning, Stefan Kiebel and colleagues from the radiochemistry department.

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