Urge to Scratch Represented in the Human Cerebral Cortex During Itch

JOURNALOFNEUROPHYSIOLOGY RAPID PUBLICATION Vol. 72. No. 6. Dcccmbcr 1994. Pritltcd111 C'.S.. I.

Urge to Scratch Represented in The Human Cerebral Cortex During Itch

JEN-CHUEN HSIEH, &TEN HAGERMARK, MONA STAHLE-BACKDAHL, KAJ ERICSON, LARS ERIKSSON, SHARON STONE-ELANDER, AND MARTIN INGVAR Department of Clinical Neuroscience, Section of Clinical Neurophysiology; Departments of Dermatology and Clinical Neuroscience,. Section sf Neuroradiology: and Karolinska Pharmacy, Karolinska Institute/Hospital, Stockholm, Sweden, and Department qf Anesthesiology, Section OfNeuroanesthesia and Pain Unit, Veterans General Hospital-Taipei, 11217 Taipei, Taiwan, Republic of. China Downloaded from SUMMARY AND CONCLUSIONS on the nature and the intensity of the stimulus (Di Piero et I. We used functional positron emission tomography (PET), al. 1994). measuring regional cerebral blood flow (rCBF) as an index of neu- The neural events leading to any target-oriented volun- ronal activity, to investigate the central processing of itch in 10 tary movement involve three processes:target identifica- healthy volunteers subjected to intracutaneous injections of hista- tion, plan of action, and execution. These three phases are mine. governed by distinct regions of the cerebral cortex: the poste-

2. The study has unraveled a central representation that depicts rior parietal cortex (PPC), the premotor areas of the frontal http://jn.physiology.org/ a motor intention of the urge to scratch contingent on the percep- cortex [supplementary motor area (SMA) together with tion of unpleasant itch. The coactivation of the anterior cingulate premotor area (PMI)], and the primary motor cortex (MI) cortex (ACC), supplementary motor area (SMA), premotor area (Ghez 1993). The urge to scratch is maintained or even (PM), and inferior parietal lobule (TPL) substantiates that the posterior sector of the ACC (Brodmann 24) is related to the sensorial/ enhanced until the itching sensation itself subsides or the affectional aspect of the event. The premotor cortical areas (SMA, scratching is done. We hypothesize that there may exist a PM) and the IPL may participate in the preparation of an in- central representation of the urge as the intention [the tended action. brain’s preparation to initiate and organize a movement to respond to a meaningful stimulus (Decety et al. 1992; Heil- man et al. 1987; Kawashima et al. 1994)] to scratch in terms by 10.220.33.2 on September 1, 2016 INTRODUCTION of sustained attention to the somatospatial information Itch and pain are unpleasant somatosensations (McMa- (right PPC) and motor planning for scratching (SMA and hon and Koltzenburg 1992) that elicit distinct defensive PM) contingent upon the perception of itch. behavior. Immediate pain elicits a reflex withdrawal while Prefrontal cortex (PFC), especially the Brodmann area itch specifically provokes scratching. The obvious purpose 46 of the dorsolateral prefrontal cortex (DLPFC), partici- of scratching is to remove harmful agents from the skin, pates in the generation of integrated motor response (Gold- thus the protective behavior has survived in evolution. man-Rakic 1987). The PFC coordinates the sensory input Hundreds of years have passed since Hafenreffer (Ha- with motor output that constitutes a purposeful behavior fenreffer 1660) made the first documented medical defini- (Fuster 1989). Since the response to itch encompassessen- tion of itch as “an unpleasant sensation with the urge to sory and motor systems, we expected the PFC, including scratch”. It is unknown, however, which supraspinal struc- DLPFC, to be involved in the intentional process of the tures are involved in the perception of itch (McMahon and urge to scratch. Koltzenburg 1992). In this study we usedfunctional PET, measuring regional In light of the neuronal nociceptive responses,the con- cerebral blood flow (rCBF) asan index of neuronal activity nections to motor system, the participation in the avoid- (Raichle 1987), to explore the central representation of itch. ance learning aswell as the richness of opioid receptors, the anterior cingulate cortex (ACC) has been proposed to partic- METHODS ipate in the affective responseto noxious stimuli (Vogt et al. Activation paradigm 1993). Direct evidence that the posterior sector of ACC (Brodmann area 24) in the human brain is involved in the Ten healthy right-handed human volunteers, range 28-49 yr perception of pain has been provided by positron emisson [mean age 4 1.5 yr; normal brain morphology verified by magnetic tomography (PET) observations (Jones et al. 199 1; Talbot resonance imaging (MRI)] participated in these experiments. et al. 199 1). Since itch and pain are both unpleasant sensa- Each subject received three intracutaneous injections of histamine (20 ~1, 10 pg/ml) and three of saline (20 ~1, 0.9%) at the lateral tions, the ACC is also a candidate for central processing of aspect of the right upper arm in a mixed, single-blind, randomized itch. Another obvious hypothesis would be the participa- manner at sites adjacent to each other but outside the rim of the tion of the contralateral primary and secondary somatosen- flare reaction. Intracutaneous injection of histamine was previ- sory areas (SI, SII) aswell asthe thalamus in the perception ously validated as a model of itch in humans and the latency, peak of itch (Shapiro and Braun 1987). However, studies on pain intensity and duration of the itch elicited were -20, 35, and 90 s have indicated that an activation of these regions depends after administration, respectively (Hagermark, 1974). The magni-

3004 0022-3077/94 $3.00 Copyright 0 1994 The American Physiological Society CEREBRAL ACTIVATION DURING ITCH 3005

Region Brodmann Area x Z-score Significance

Left hemisphere Superior frontal gyrus 6/32 (SMA) -4 -4 51 2.513 <0.05 Middle frontal gyrus 6 (PM) -42 10 51 2.869

Middle frontal gyrus 6 (PM) 34 0 57 2.595 co.05 Downloaded from Superior frontal gyrus 8 12 20 51 3.5 14

Middle frontal gyrus 46 41 42 8 3.386

Brain regions activated during itch. The anatomic structures are called in from the database of the CBA. Coordinates of peak activation are expressed in millimeters (Talairach a .nd Tournoux 1988). X, med ial-lateral relative to midline (positive = right): J’, anterior-posterior relative to a nterior commissu re (positive = anterior); z, superior-inferior relative to commissural line (positive = superior): SMA, su pplementary motor area; PM, premotor area. tude of itch [rated with a loo-mm Visual Analogue Scale (VAS)] var et al. 1994) corrected for multiple comparison (Friston et al. and the urge to scratch (presence or absence) were recorded after 1991). each rCBF measurement. Each subject underwent six scans - 10 by 10.220.33.2 on September 1, 2016 min apart and was instructed to remain still with eyes closed dur- RESULTS ing the scanning. Following histamine injections, all subjects reported a pure sensation of itch (32.7 t 16.2 by VAS, similar to a PET scanning mosquito bite) with the presence of an urge to scratch. They rCBF ( 100-s summation image) was measured with the intrave- would have scratched the area of injection had they not nous [ 150]butanol technique on a Scanditronix-PC2048 system been instructed to remain still during the scanning. No sub- while using stereotactic fixation of the subject’s head (Ingvar et al. ject reported such a reaction after the saline injection. 1994). [ 150]Butanol (28-32 mCi [ 1.03- 1.18 GBq), iv] was injected The activation was not due to anxiety, since subjects re- 8- 10 s after the administration of histamine or saline. The time ported little emotional reaction to the paradigm. We ob- elapsed between the injection of isotope and the commencement of cerebral tissue activity was 14- 18 s, and the cerebral radioactiv- served activation of the left ACC (Brodmann area 24), right ity peaked 40-50 s after the administration of isotope. The proto- inferior parietal cortex (IPL: Brodmann area 39/40) of the col was thus optimized to catch the peak itch sensation at the PPC, bilateral SMA (more prominent on the right side) and approximate time of the bolus arrival of rCBF tracer to the brain. PM, aswell as right DLPFC (Brodmann area 46) of the PFC (Table 1, Fig. 1). The proposed affectional representation of Image analysis and statistical treatment unpleasant sensation (ACC: Brodmann area 24) was contralaterally activated while structures pertinent to the motor These images were reformatted, using an adjustable computer- intention and programming (SMA, PM) were more ipsilat- ized brain atlas (CBA) (Greitz et al. 199 1) for stereotactic standard- erally expressed.These findings contrast with the coactiva- ization and subsequently normalized to give a global uptake of 50 tion of contralateral ACC and SMA in a recent study of nCi/ml. Twenty-eight out of 30 (2 discarded due to technical fail- pain (Coghill et al. 1994). We also observed activation of ure) individual-paired pixel-by-pixel subtraction images (histamine vs. saline) were averaged and filtered with 12 mm FWHM some other regions of the association cortex and cerebellum Gaussian filter to generate a state-dependent, averaged rCBF as well as the right red nucleus (RN). We did not observe a change and error images (Ingvar et al. 1994). The regions-of-inter- significant change in rCBF in the SI, SII, or in the thalamus. est (pixel-by-pixel) were drawn guided by anatomic structures from the brain database of the CBA. The p-map (Fig. 1) was con- DISCUSSION structed on the basis of the conventional statistical Student’s t-test (t-map) and created by assigning different colors depending on the The cerebral activation pattern confirms our prediction t-value and probability factor of a pixel. The t-map was then trans- about the afferent and the efferent component of the cen- ferred to a z-score map and the final designation of significant tral processing of itch. The pronounced activation in the change was based on the calculated local z-score maximum (Ing- contralateral ACC (Brodmann area 24) reflects the unpleas- Downloaded from c http://jn.physiology.org/ by 10.220.33.2 on September 1, 2016

I I CEREBRAL ACTIVATION DURING ITCH 3007 ant nature of itch (Table 1; Fig. 1c). The so-called “itch Goldman-Rakic 1987; Pardo et al. 199 1). Brodmann area center” has long been proposed to be at the medulla oblon- 46 has reciprocal connections (Pandya and Yeterian 1990) gata due to the relationship between itch and opioids to all the activated regions pertinent to motor programming (Koenigstein 1948). However, our findings strongly suggest (SMA, PM, and IPL) and could, through these connections, that the ACC (Brodmann area 24) also subserves the pro- participate in the timing and/or direction of motor output cessing of itch. Lack of rCBF changes in the SI, SII, and the (Funahashi et al. 1993; Fuster 1989; Goldman-Rakic thalamus may be ascribed to the insufficient intensity of the 1987). In addition, motor planning activity can also be re- itch elicited with current paradigm. As has been revealed by corded in DLPFC (Funahashi et al. 1993) and lesions here the brain imaging studies of pain, sufficient intensity of the induce hypokinesia (Fuster 1989; Goldman-Rakic 1987). stimulus is mandatory to activate these regions (Di Piero et Thus the prominent activation of the right DLPFC (Brod- al. 1994). mann area 46, activation extends 33 mm axially) may re- Evidence that the urge to scratch may contain a central flect the organization of the motor response to itch. representation of intention is provided by the coactivation In conclusion, the central activation profile demon- of the right inferior parietal lobule (IPL), bilateral SMAs strated here supports Hafenreffer’s definition of itch as “an and PMs (Table 1; Fig. 1, B-C). The activation of only the unpleasant sensation with the urge to scratch”. The activa- right IPL (Brodmann area 40, 39) which is a main part of tion of both the ipsilateral SMA and contralateral ACC dur- Downloaded from the right PPC, is in accordance with a right hemispheric ing itch contrasts the findings of activation of both the SMA lateralization for somatospatial information (Heilman et al. and ACC contralaterally during pain (Coghill et al. 1994). 1987; Kolb and Whishaw 1990). Patients with lesions in the This distinction could account for the behavioral difference right IPL, which effectuates motor movement under sen- of approach and avoidance in itch and pain, respectively. It sory guidance, have severe attentional disturbances, re- also substantiates that the posterior sector of the ACC

ferred to as sensory neglect syndrome (Heilman et al. 1987; (Brodmann area 24) is related to the sensorial/affectional http://jn.physiology.org/ Kolb and Whishaw 1990). The coactivations of the SMA aspect of the event (Vogt et al. 1993) while the premotor and PM found here may reflect the readiness of initiation to areas (SMA, PM) may participate in the preparation of an act (Fox et al. 1985) and are consistent with recent func- intended action (Goldberg 1985). tional MRI (Rao et al. 1993) and electrophysiological studies. Programming or imaging a complex motor task acti- Special thanks to W. Pulka, P. Soderholm, and G. Printz, B.-M. Berg- vates the SMA and/or PM (Rao et al. 1993). The Bereit- gren, M. Serrander, and K. Rehnquist for technical and administrative support. schafts potential (Deecke 1990) (readiness potential) This work was sponsored by the Swedish Medical Research Council elicited immediately before willed movement, can be re- (8276,9847), the Karolinska Institute, the Loo and Hans Osterman Foun- corded from the human SMA during pure internal plan- dation, the Edvard Welander Foundation, and the Finsen Foundation. by 10.220.33.2 on September 1, 2016 ning without motor execution (Libet et al. 1983). Motor Address for reprint requests: M. Ingvar, Dept. of Clinical Neuroscience, planning activity can be recorded in the SMA and PM dur- Sect. of Clinical Neurophysiology, Karolinska Hospital, S- 17 1 76 Stock- holm, Sweden. ing a preparation to act (Kurata and Wise 1988). The bihe- mispheric activation of the SMA and PM is in agreement Received 1 1 July 1994; accepted in final form 29 August 1994. with a bilateral elaboration of the motor program for complex movement (Goldberg 1985). Nevertheless, the contra- REFERENCES lateral SMA has been shown to be more expressed than the ipsilateral SMA for motor programming in recent func- COGHILL, R. C., TALBOT, J. D., EVANS, A. C., MEYER, E., GJEDDE, A., tional MRI (Rao et al. 1993) as well as intracerebral electro- BUSHNELL, M. C., AND DUNCAN, G. H. Distributed processing of pain and vibration by the human brain. J. Neurosci. 14: 4095-4 108, 1994. physiological studies (Ikeda et al. 1992). Thus, the more COLEBATCH, J. G., DEIBER, M., PASSINGHAM, R. E., FRISTON, K. J., AND pronounced activation in the right SMA (activation lies in FRACKOWIAK, R. S. J. Regional cerebral blood flow during voluntary the border zone of Brodmann area 6 and the Brodmann arm and hand movements in human subjects. J. Nwrophysioj. 65: area 32 of the dorsalmost ACC: motor representation of 1392-1401, 1991. arm in the medial frontal cortex) (Colebatch et al. 199 1; DECETY, J., KAWASHIMA, R., GULYAS, B., AND ROLAND, P. E. Prepara- tion for reaching: a PET study of the participating structures in the Dum and Strick 1993) may indicate the intention of the left human brain. Nezrroreport 3: 76 l-764, 1992. hand to scratch the injection site on the upper right arm. DEECKE, L. Electrophysiological correlates of movement initiation. Rev. Our findings and interpretation are consistent with recent New)/. 146: 6 12-6 19, 1990. PET studies of the motor preparation for target-reaching, in DUM, R. P. AND STRICK, P. L. Cingulate motor areas. In: Neurobiology qf Cingulute Cortex und Limhic Thalamus, edited by B. A. Vogt and M. which the IPL (supramarginal and angular gyri) and the Gabriel. Boston: Birkhauser, 1993, p. 415-444. premotor areas (SMA, PM) prevailed (Decety et al. 1992; Fox, P. T., Fox, J. M., RAICHLE, M. E., AND BURDE, R. M. The role of Kawashima et al. 1994). The activation of the RN (Table 1; cerebral cortex in the generation of voluntary saccades: a positron emis- Fig. IF is interesting since there are known projections of sion tomographic study. J. Nezrrophysiol. 54: 348-369, 1985. the limb-control system to this area from three motor cor- FRISTON, K. J., FRITH, C. D., LIDDLE, P. F., AND FRACKOWIAK, R. S. J. Comparing functional (PET) images: the assessment of significant tices (Brodmann area 4, 6, and 8) and the PPC (Kuypers change. J. Cereh. Blood Fk.,w Metah. 1 1: 690-699, 199 1. 1981). FUNAHASHI, S., CHAFEE, M. V., AND GOLDMAN-RAIUC, P. Prefrontal neu- We recorded an extensive activation of the bilateral PFC ronal activity in rhesus monkeys performing a delayed anti-saccade task. (Brodmann area 8, 9, 10, 32,44,45, and 46) in response to Nutwe Lond. 365: 753-756, 1993. FUSTER, J. M. The prefrontal cortex: anatomy, physiology and neuropsy- itch (Fig. 1, B-F; Table 1). These regions subserve diverse chology of the frontal lobe. New York: Raven Press, 1989, p. l-255. functions, such as sustained attention, associative process- GHEZ, C. Voluntary movement. In: Principles qfNeura1 Science, edited by ing, and preparation of the motor reaction (Fuster 1989; E. R. Kandel and J. H. Schwartz. New York: Elsevier, 1993, p. 609-625. 3008 HSIEH ET AL.

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