Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation

DOI: 10.1093/brain/awg102 Brain (2003), 126, 1079±1091 Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation J. Lorenz,1,3,5 S. Minoshima4 and K. L. Casey1,2,3 Departments of 1Neurology and 2Physiology, University of Michigan, 3Neurology Research Laboratories, Veterans Affairs Medical Center, Ann Arbor, MI, 4Radiology Department, University of Washington, Seattle, WA, USA and 5Institute of Physiology, University of Hamburg, Hamburg, Germany Summary Frontal lobe activity during pain is generally linked to attentional processing. We addressed the question of whether `bottom-up' processing and `top-down' modulation of nociceptive information dissociate anatomically within the frontal lobe by using PET scanning during painful thermal stimulation of normal and capsaicintreated skin. We showed recently that pain following normally non-painful heat stimuli on chemically irritated skin (heat allodynia) uniquely engages extensive areas of the bilateral dorsolateral prefrontal (DLPFC), ventral/orbitofrontal (VOFC) and perigenual anterior cingulate (ACC) cortices. Here, we applied principal component analysis (PCA) and multiple regression analysis to study the covariance structure of the volumes of interest (VOI) activated speci®cally during heat allodynia in 14 male healthy subjects and evaluated the relationship of these VOI to ratings of pain intensity and affect. Results yielded a primary principal Correspondence to: PD Dr med. JuÈrgen Lorenz, Institut fuÈr Neurophysiologie und Pathophysiologie, UniversitaÈtsklinikum Eppendorf Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany E-mail: component (PC) that correlated positively with intensity and unpleasantness and accounted for activity in the medial thalamus, bilateral anterior insula, ventral striatum, perigenual ACC and bilateral VOFC. Activities in the right and left DLPFC loaded on separate PC and correlated negatively with perceived intensity and unpleasantness. The inter-regional correlation of midbrain and medial thalamic activity was signi®cantly reduced during high left DLPFC activity, suggesting that its negative correlation with pain affect may result from dampening of the effective connectivity of the midbrain±medial thalamic pathway. In contrast, right DLPFC activity was associated with a weakened relationship of the anterior insula with both pain intensity and affect. We propose that the DLPFC exerts active control on pain perception by modulating corticosubcortical and corticocortical pathways. Keywords: pain modulation; capsaicin; functional neuroimaging; prefrontal cortex; effective connectivity Abbreviations: ACC = anterior cingulate cortex; DLPFC = dorsolateral prefrontal cortex; HPTc = heat pain threshold on sensitized skin; HPTn = heat pain threshold on normal skin; PCA = principal component analysis; rCBF = regional cerebral blood ¯ow; VOFC = ventral/orbitofrontal cortex; VAS = visual analogue scale; VOI = volume of interest Introduction The CNS is capable of altering sensitivity to painful stimuli. Endogenous pain inhibition is believed to account for the considerable ¯uctuation of pain that occurs over very short periods of time. The biological signi®cance of endogenous pain control is generally seen in the context of behavioural con¯icts in which the individual needs to disengage from pain in order to ®ght or escape in the presence of body injury (Melzack and Casey, 1968). Analogous human life situations are sporting competition and combat, during which a subject ã Guarantors of Brain 2003 may fail to be aware of even severe tissue damage, which becomes painful when the victim releases engagement in these activities. Whereas the spinal and medullary mechanisms of inhibitory control of nociceptive transmission have been the focus of extensive research since pioneering work by Melzack and Wall (1965), Basbaum and Fields (1978) and Le Bars et al. (1979), we have an incomplete understanding of how higher cortical functions contribute to endogenous pain control. Because pain is dif®cult to ignore and interferes with 1080 J. Lorenz et al. Table 1 Time schedule of events in the PET scanner Time (min) Group A Group B ±10 0 15 30 45 60 70±100 110 115 125 140 155 170 175 HPTn Rest HPTn ± 2°C HPTn + 2°C HPTn + 2°C HPTn ± 2°C Capsaicin treatment Rest HPTc HPTn ± 2°C HPTn + 2°C HPTn + 2°C HPTn ± 2°C HPTc HPTn Rest HPTn + 2°C HPTn ± 2°C HPTn ± 2°C HPTn + 2°C Rest HPTc HPTn + 2°C HPTn ± 2°C HPTn ± 2°C HPTn + 2°C HPTc Average HPTn = 45.5 6 1.6°C (SD); average HPTc = 41.1 6 1.9°C. concurrent activities (Lorenz and Bromm, 1997; Eccleston and Crombez, 1999; Casey and Lorenz, 2000), the involvement of higher cortical functions may constitute a way of resolving cognitive and behavioural con¯icts by allowing competing task-relevant stimuli to dominate over pain. A likely candidate brain area to coordinate pain modulation with goal-directed behaviour is the frontal lobe. Evidence suggests that the dorsolateral prefrontal cortex, comprising Brodmann areas 9 and 46, is important for continuous monitoring of the external world, maintenance of information in short-term memory and governing ef®cient performance control in the presence of interfering stimuli (MacDonald et al., 2000; Bunge et al., 2001; Sakai et al., 2002). Furthermore, electrical stimulation of ®bre connections of the prefrontal cortex to the midbrain mediates antinociceptive effects in rodents (Cooper, 1975; Hardy and Haigler, 1985; Zhang et al., 1998). However, the frontal lobe may not have a unitary role in pain processing, as orbitofrontal and medial frontal lesions diminish pain-related behaviours in animals (Reshetniak and Kukushkin, 1989; Pastoriza et al., 1996). Non-invasive neuroimaging studies using PET and functional MRI allow us to examine the involvement of the frontal lobe in human pain perception. Various groups describe prefrontal cortex activity following experimental (Casey et al., 1996; Iadorola et al., 1998; Paulson et al., 1998; Baron et al., 1999; ToÈlle et al., 1999) or clinical (Hsieh et al., 1996; Rosen et al., 1996; Silverman et al., 1997) pain conditions. Frontal lobe activity during pain is generally related to cognitive and attentional processing of painful stimuli (Coghill et al., 1999; Casey, 1999; Peyron et al., 1999; BornhoÈvd et al., 2002). There is evidence that medial prefrontal areas and the perigenual anterior cingulate cortex (ACC) are activated by expectancy of pain (Ploghaus et al., 1999; Sawamoto et al., 2000), the interaction of pain with anxiety (Ploghaus et al., 2001), placebo cognitions (Petrovic et al., 2002) and cognitively demanding tasks (Petrovic et al., 2000; Bantick et al., 2002). We recently found substantial prefrontal cortex activation involving bilateral activity of the orbitofrontal, perigenual cingulate and dorsolateral prefrontal cortices using PET during heat stimuli on capsaicin-treated skin (Lorenz et al., 2002). In this study, we compa (...truncated)