Burning questions about the brain in pain by Stuart Derbyshire | Papers by Stuart

Pain 122 (2006) 217–218 www.elsevier.com/locate/pain Editorial Burning questions about the brain in pain In this issue, Albuquerque et al. (2006) describe brain activation during noxious thermal stimulation in patients with burning mouth disorder (BMD). Eight patients and eight matched controls were studied using fMRI in conjunction with a heat probe applied to the right side of the face. The heat probe delivered pulses of noxious heat (47–49 °C) interspersed by periods of continuous warmth (39.5 °C) or neutral (32 °C) stimulation. They found that the BMD patients had greater activation during noxious heat in the anterior cingulate cortex (ACC) but lesser activation in right and left thalamus and in various regions of the frontal cortex. The authors comment that the ‘‘general appearance is that of greater and more spatially extensive areas of activation in normal subjects as compared to BMD patients’’. Generally reduced activation in patients with ongoing pain has been commented upon previously (Derbyshire, 1999; Apkarian et al., 2005) and implies that the presence of ongoing clinical pain alters brain processing of acute pain. There are several possible explanations for the reduced activation in patients suffering ongoing pain: Brain responses in pain patients may already be elevated and the activation due to additional pain may be limited by the relatively higher baseline activation; patient populations may be more heterogeneous than control subjects, with a more varied brain response to pain, resulting in a reduced average response across patients; brain tissue may habituate, and even whither away (Apkarian et al., 2004), when receiving continual noxious input; areas of the brain that normally provide pain inhibition may be inactive in pain patients, perpetuating their condition. These possibilities are not mutually exclusive and the list is by no means exhaustive. Stroke victims with damage to the thalamus can report disturbing pain syndromes contralateral to the damage (Bowsher, 2005), which may be a consequence of disturbed descending inhibition of pain. The reduced thalamic activation observed in patients with BMD could, therefore, be causally involved in the pain experi- enced by BMD patients. Although plausible, this interpretation is highly speculative and leaves many unanswered questions. The percentage of studies with normal volunteers reporting an absence of thalamic response is about 20%, which compares to about 40% of patient studies (Apkarian et al., 2005). These statistics imply a possible failure of active thalamic inhibition in clinical pain populations but the effect is certainly inconsistent. Furthermore, there is considerable variability in the brain response to noxious stimulation across individuals (Vogt et al., 1996; Kwan et al., 2000) and the relationship between this normal variability and the potentially abnormal responses of patients remains unclear. More specifically, without any direct verification of thalamic hypoactivity being involved in pain generation, the meaning of reduced thalamic response in the Albuquerque study remains very uncertain. It is intriguing that Albuquerque et al. (2006) have replicated earlier findings of ACC hyperactivity in chronic pain patients; their pattern of results is especially similar to the pattern we previously observed with atypical facial pain (Derbyshire et al., 1994). It is tempting to speculate that cortical dysfunction, involving reduced frontal and increased ACC responses, may be directly responsible for types of chronic facial pain. Such speculation needs to be tempered by the small number of studies, involving relatively few patients, which have shown this pattern of response. There are also several studies involving related pain disorders that have shown quite different responses (Silverman et al., 1997; Mertz et al., 2000; Gracely et al., 2002; Giesecke et al., 2004). The variability in the results from brain imaging studies is bound to be in part due to methodological differences. There is a broad heterogeneity of patients, methods of stimulation and techniques of imaging that will have an influence on the experience of pain and the subsequent activation of brain regions. This can be stated less kindly; that there has been fairly loose control over the experimental conditions that may influence 0304-3959/$32.00 Ó 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.pain.2006.02.031 218 Editorial / Pain 122 (2006) 217–218 Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 2004;24:10410–5. Bowsher D. Allodynia in relation to lesion site in central post-stroke pain. J Pain 2005;6:736–40. Coghill RC, Sang CN, Maisog JMA, Iadorola MJ. Pain intensity processing within the human brain: a bilateral, distributed mechanism. J Neurophysiol 1999;82:1934–43. Derbyshire SWG. Meta-analysis of thirty-four independent samples studied using positron emission tomography (PET) reveals a significantly attenuated central response to noxious stimulation in clinical pain patients. Curr Rev Pain 1999;3:265–80. Derbyshire SWG, Jones AKP, Gyulai F, Clark S, Townsend D, Firestone L. Pain processing during three levels of noxious stimulation produces differential patterns of central activity. Pain 1997;73:431–45. Derbyshire SWG, Jones AKP, Devani P, Friston KJ, Feinmann C, Harris M, et al. Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography. J Neurol Neurosurg Psychiatry 1994;57:1166–72. Giesecke T, Gracely RH, Grant MA, Nachemson A, Petzke F, Williams DA, et al. Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthrit Rheum 2004;50:613–23. Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, et al. Pain catastrophizing and neural responses to pain among persons with fibromyalgia. Brain 2004;127:835–43. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthrit Rheum 2002;46:1333–43. Kwan CL, Crawley AP, Mikulis DJ, Davis KD. An fMRI study of the anterior cingulate cortex and surrounding medial wall activations evoked by noxious cutaneous heat and cold stimuli. Pain 2000;85:359–74. Lorenz J, Casey KL. Imaging of acute versus pathological pain in humans. Eur J Pain 2005;9:163–5. Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distension. Gastroenterology 2000;118:842–8. Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997;112:64–72. Tracey I, Ploghaus A, Gati JS, Clare S, Smith S, Menon RS, et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. J Neurosci 2002;22:2748–52. Vogt BA, Derbyshire SWG, Jones AKP. Pain processing in four regions of human cingulate cortex localized with co-registered PET and MR imaging. Eur J Neurosci 1996;8:1461–73. pain experience and thus the areas of activation observed. More recent studies have begun to manipulate the factors that may influence pain experience in an effort to uncover what the various parts of the pain activation matrix may be doing and, by implication, why they may not always be present, or may be over-present, in chronic pain populations (Tracey et al., 2002; Gracely et al., 2004; Lorenz and Casey, 2005). These advances in experimental technique are important because they also narrow the theoretical framework and so constrain the results and the interpretation. The dominant themes in the interpretation of many chronic pain disorders include hypersensitivity, hypervigilance, hyperalgesia, central sensitization, stress mediated dysfunction and, encompassing all these themes, the biopsychosocial model. These concepts are broad and dependent on multiple components that are rarely directly addressed by any single study. Consequently, almost any pattern of brain activation can be easily integrated into current conceptual thinking while remaining indeterminate as a source of evidential relevance for any component of the disease experience. Hypervigilance, for example, has been attached to increased ACC (Derbyshire et al., 1994; Gracely et al., 2004), decreased ACC (Silverman et al., 1997) and normal ACC (Mertz et al., 2000) responses to noxious stimulation. Broad descriptive studies such as that by Albuquerque remain interesting and useful but studies that focus on hypothesized regional responses to psychophysically well-controlled stimuli have a better chance at explaining the underlying neuropsychology of chronic pain. Studies with normal volunteers have demonstrated that greater pain experience from a nociceptive stimulus results in proportionately greater brain activation (Derbyshire et al., 1997; Coghill et al., 1999). The study by Albuquerque et al. (2006) adds to the evidence that in chronic pain populations there is a less proportionate relationship between pain experience and activation. That less proportionate relationship awaits explanation. References Albuquerque RJC, de Leeuw R, Carlson CR, Okeson JP, Miller CS, Andersen AH. Cerebral activation during thermal stimulation of patients who have burning mouth disorder: an fMRI study. Pain 2006;122:223–34. Apkarian AV, Bushnell MC, Treede R-D, Zubieta J-K. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005;9:463–84. S.W.G. Derbyshire * University of Birmingham, School of Psychology, Edgbaston, B15 2TT, United Kingdom E-mail address: derbyshiresw@bham.ac.uk * Tel.: +44 121 414 4659; fax: +44 121 414 4897.