fMRI reveals distinct CNS processing during symptomatic and recovered complex regional pain syndrome in children

doi:10.1093/brain/awn123 Brain (2008), 131, 1854 ^1879 fMRI reveals distinct CNS processing during symptomatic and recovered complex regional pain syndrome in children A. Lebel,1 L. Becerra,2,3,4,5 D. Wallin,2 E. A. Moulton,2 S. Morris,2 G. Pendse,2 J. Jasciewicz,1 M. Stein,1 M. Aiello-Lammens,2 E. Grant,3 C. Berde2 and D. Borsook2,3,4,5 P.A.I.N. Group of 1Department of Anesthesia, Children’s Hospital Boston, 2Department of Psychiatry, McLean Hospital, 3 Massachusetts General Hospital, 4Department of Radiology, Children’s Hospital Boston and 5Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Belmont, MA, USA Correspondence to: David Borsook, MD, PhD, P.A.I.N. Group, McLean Hospital, 115 Mill Street, Belmont MA E-mail: Complex regional pain syndrome (CRPS) in paediatric patients is clinically distinct from the adult condition in which there is often complete resolution of its signs and symptoms within several months to a few years. The ability to compare the symptomatic and asymptomatic condition in the same individuals makes this population interesting for the investigation of mechanisms underlying pain and other symptoms of CRPS.We used fMRI to evaluate CNS activation in paediatric patients (9^18 years) with CRPS affecting the lower extremity. Each patient underwent two scanning sessions: once during an active period of pain (CRPS+), and once after symptomatic recovery (CRPS2). In each session, mechanical (brush) and thermal (cold) stimuli were applied to the affected region of the involved limb and the corresponding mirror region of the unaffected limb.Two fundamental fMRI analyses were performed: (i) within-group analysis for CRPS+ state and CRPS2 state for brush and cold for the affected and unaffected limbs in each case; (ii) between-group (contrast) analysis for activations in affected and unaffected limbs in CRPS or post-CRPS states. We found: (i) in the CRPS+ state, stimuli that evoked mechanical or cold allodynia produced patterns of CNS activation similar to those reported in adult CRPS; (ii) in the CRPS+ state, stimuli that evoked mechanical or cold allodynia produced significant decreases in BOLD signal, suggesting pain-induced activation of endogenous pain modulatory systems; (iii) cold- or brushinduced activations in regions such as the basal ganglia and parietal lobe may explain some CNS-related symptoms in CRPS, including movement disorders and hemineglect/inattention; (iv) in the CRPS^ state, significant activation differences persisted despite nearly complete elimination of evoked pain; (v) although non-noxious stimuli to the unaffected limb were perceived as equivalent in CRPS+ and CRPS2 states, the same stimulus produced different patterns of activation in the two states, suggesting that the ‘CRPS brain’ responds differently to normal stimuli applied to unaffected regions. Our results suggest significant changes in CNS circuitry in patients with CRPS. Keywords: children; pain; fMRI; plasticity; reflex sympathetic dystrophy Abbreviations: CRPS = complex regional pain syndrome; RSD = reflex sympathetic dystrophy; VAS = visual analog score; GMM = Gaussian mixture modelling Received January 17, 2008. Revised May 12, 2008. Accepted May 15, 2008. Advance Access publication June 20, 2008 Introduction In adults, complex regional pain syndrome (CRPS) is a clinical syndrome featuring severe pain, hypersensitivity to innocuous (allodynia) and noxious (hyperalgesia) somatosensory stimuli, autonomic/neurovascular signs (coldness, poor circulation, abnormal sweating, swelling and skin discolouration) and trophic signs (abnormal hair and nail growth, muscle atrophy, joint contractures) (Wasner et al., 1998; Sieweke et al., 1999; Birklein et al., 2000). Though the pathophysiology of CRPS has not been clearly defined, it has been suggested to be a form of painful small fibre sensory neuropathy (Santiago et al., 2000). CRPS types I and II correspond approximately to the older terms ‘reflex sympathetic dystrophy’ (RSD) ß The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: fMRI of CNS in paediatric CRPS: temporal changes and ‘causalgia’, respectively (Grabow et al., 2004), but may in fact be similar diseases (Oaklander et al., 2006). CRPS, as a chronic neuropathic pain syndrome, likely involves peripheral and central sensitization of neuronal function (Janig and Baron, 2002). At the level of the spinal cord and brainstem, these disturbances are thought to be related to the altered neuroplasticity that leads to abnormal central pain processing (Porreca et al., 2002; Dubner, 2004). Current thinking is that CRPS is a disease of the CNS (Janig and Baron, 2002) with a phenotype that includes alterations in autonomic function (Birklein et al., 1998; Meier et al., 2006); sensory systems (Drummond and Finch, 2006; Maihofner et al., 2006b), as indicated by pain that progresses from its initial site proximally up a limb and even to the contralateral side (Maleki et al., 2000); and motor systems (Verdugo and Ochoa, 2000), as indicated by associated dystonia and movement disorders. Higher level functions such as visuospatial perception are also involved (Sumitani et al., 2007), as indicated by neglect-like symptoms (Galer et al., 1995; Galer and Jensen, 1999; Frettloh et al., 2006; Maihofner and DeCol, 2007). Recent studies investigated alterations in brain function in adult patients with CRPS (Maihofner et al., 2003, 2005, 2006a; Pleger et al., 2006). Von–Frey stimulation of the affected limb evoked pinprick hyperalgesia and produced greater contralateral activation than identical stimulation of the unaffected limb in primary (S1) and secondary (S2) sensory cortex, insula, anterior cingulate cortex and frontal cortices (Maihofner et al., 2005). Mechanical allodynia evoked by brushing the affected limb was reported to correspond with activation of motor (M1) and cognitive regions (frontal regions), areas involved in emotional processing (e.g. anterior and posterior cingulate cortex, temporal lobe), parietal association cortices, as well as pain sensory regions (e.g. S1, insula) (Maihofner et al., 2006a). Of note was the significant negative activation in visual, posterior insular and temporal cortices in response to brushing that evoked allodynia. Other types of chronic pain, such as phantom limb pain, have been shown to produce significant cortical reorganization (Flor et al., 1995; Karl et al., 2001). In a recent study using magnetic source imaging, cortical reorganization was reported in the contralateral SI cortex in patients with CRPS (Maihofner et al., 2004). The reorganization involved parts of the body (lips and fingers) that did not have pain, but exchanged representations following recovery from CRPS. An fMRI study also demonstrated cortical reorganization in CRPS: BOLD signals in contralateral S1 and S2 induced by innocuous electrical (...truncated)