1. INTRODUCTION Chronic pain is associated with cortical functional, neurochemical and morphological changes (Grachev et al., 2002, Apkarian et al., 2004). Complex regional pain syndrome (CRPS) is a chronic neuropathic pain condition characterized mainly by spontaneous and evoked pain, autonomic abnormalities and depression. CRPS patients fail to learn a specific emotional decision making task similar to stroke patients with lesions in the medial prefrontal cortex (VMPFC). We hypothesized therefore that CRPS patients have brain atrophy in areas mediating emotional decision making like the VMPFC. Here, we examine the structural inter- relationship between gray and white matter in CRPS patients and matched healthy controls using gray matter volumetric and density parameters and white matter water diffusion measurements using diffusion tensor imaging (DTI) Funded by NIH NINDS NS35115 The brain in chronic CRPS pain: Abnormal gray-white matter interactions in emotional and autonomic areas P. Y. GEHA 1, M. N. BALIKI 1, N. R. HARDEN 2, T. B. PARRISH 3, W. R. BAUER 4, *A. V. APKARIAN 1 ; 1 Dept of Physiol, 2 RIC, 3 Dept of Radiology, Northwestern Univ. Med. Sch., Chicago, IL; 4 Neurosci., Univ. of Toledo, Toledo, OH METHODS Twenty-three CRPS patients and 21 age and gender matched normal controls participated in this study. CRPS patients were diagnosed based on IASP criteria. Only patients who had a pain intensity of at least 3/10 on the VAS, and a history of at least 3 months of CRPS were recruited for this study. Subjects underwent whole brain diffusion tensor imaging (DTI) in a 3T magnet in two interleaved scans. Data was acquired with bvecs = 60 different directions, and vector strength of b = 1000 s.mm -2, with a 1.7×1.7×2 voxel dimensions. T1 images were acquired using the MPRAGE protocol with 1 x 1 x 1 mm dimensions. Whole brain gray matter volume was determined using SIENAX from FSL toolbox (Smith et al., 2002) DTI was analyzed using the Diffusion Toolbox (FDT) of FSL (FMRIB, Oxford). (Behrens et al., 2003). Statistical analysis of FA maps was carried using TBSS) (Smith et al., 2006). CRPS patients exhibited a disrupted relationship between white matter anisotropy and whole-brain gray matter volume Gray matter atrophy in CRPS was limited to a single cluster encompassing right insula, right ventromedial prefrontal cortex, and right nucleus accumbens Decrease in fractional anisotropy was observed in the left cingulate-callosal bundle. Reorganization of white matter connectivity was characterized by branching pattern alterations and global loss of connectivity. Changes in gray and white matter properties were correlated to clinical characteristics of CRPS These abnormalities encompass emotional, autonomic, and pain perception regions, implying that they likely play a critical role in the global clinical picture of CRPS. CONCLUSION SFN 2008 Washington 175.25 Whole-brain cortical gray volume and white matter anisotropy 1 A. Skull normalized, neocortical gray matter volume in healthy (left) and CRPS patients (right) shown as a function of age. B. Whole-brain fractional anisotropy (mean FA calculated over individual subjects ’ white matter skeleton), a global measure of water diffusion over white matter tracks, in relation to whole-brain neocortical gray matter volume. The significant correlation between the two measures in healthy subjects is absent in CRPS. (* p < 0.05; ** p < 0.01) c Regional gray matter density is decreased in CRPS and related to pain characteristics 2 A. CRPS exhibit decreased density within the ventromedial prefrontal cortex (VMPFC), anterior insula (AI), and nucleus accumbens (p < 0.05 corrected). The scatter plot shows that this gray matter density is negatively correlated to the number of years the patients have been living with CRPS. The histogram depicts mean (± SEM) gray matter density within the cluster in both groups. B. VMPFC gray matter density negatively correlated to the interaction between pain intensity and pain duration C. AI gray matter density only correlated to pain duration Decreased regional anisotropy and connectivity in CRPS 3 A. Decreased FA in CRPS, localized to a portion of the left callosal fibers (purple). The histogram depicts mean FA (± SEM for the two groups, for the white matter region showing decreased FA. B. Population maps of results of probabilistic tractography when the white matter region showing decreased FA was used as the seed. The tract traversing posteriorly in the healthy subjects belongs to the cingulate bundle and seems diminished in the CRPS patients. C. Group averaged number of connections as a function of Euclidean (left). First histogram shows total number of connections from the seed, and second histogram (thinner bars) the fractal dimension Df of branching of connections. Association between gray and white matter changes in the VMPFC 4 A. Probabilistic maps of VMPFC white matter tracts for Normals and CRPS B. Connections as a function of distance, total connections and fractal dimension (See Panel 3).. C. In CRPS, target connectivity is significantly higher to the insula (Ins) and lower to the basal ganglion (BG), but unchanged to the thalamus (Thal), primary somatosensory cortex (SI) and visual cortex (Vis) 5 A. Probabilistic maps of AI white matter tracts for Normals and CRPS B. Connections as a function of distance, total connections and fractal dimension (See Panel 3).. C. In CRPS, target connectivity is significantly lower to to the basal ganglion (BG), but unchanged to the VMPFC, thalamus (Thal), primary somatosensory cortex (SI) and visual cortex (Vis). Association between gray and white matter changes in the Insula