Supplemental Material.Pdf

Home , Brodmann area, Brodmann area 46, Brodmann area 8, Cerebrum, Cuneus, Frontal lobe

Decreased rCBF with 60mg bid SYN115 See legend at bottom of table.

cluster-level voxel-level atlas location

pFWE-corr qFDR-corr kE puncorr pFWE-corr qFDR-corr T Zequiv puncorr Xmm Ymm Zmm cluster # VOI Nearest gray matter according to Talairach Daemon (last number = distance in mm) 1 0.000 0.000 1387 0.000 0.000 0.005 19.51 6.17 0.000 10.5 -21 12 1 Right Cerebrum,Sub-lobar,Thalamus,Gray Matter,Medial Dorsal Nucleus,0 0.000 0.016 15.36 5.75 0.000 -7.5 -18 12 2 Left Cerebrum,Sub-lobar,Thalamus,Gray Matter,Medial Dorsal Nucleus,0 0.001 0.029 12.91 5.44 0.000 13.5 -66 36 3 Right Cerebrum,Parietal Lobe,Precuneus,Gray Matter,Brodmann area 7,1 0.005 0.059 11.37 5.20 0.000 1.5 -60 21 Right Cerebrum,Occipital Lobe,Precuneus,Gray Matter,Brodmann area 23,1 0.006 0.063 11.00 5.14 0.000 19.5 -72 39 Right Cerebrum,Parietal Lobe,Precuneus,Gray Matter,Brodmann area 7,1 0.023 0.111 9.68 4.89 0.000 10.5 -36 -12 midbrain, edge of brain 0.034 0.121 9.32 4.81 0.000 -4.5 -33 -3 4 midbrain (superior colliculus per Mai atlas) 0.039 0.121 9.20 4.79 0.000 -7.5 -24 6 Left Cerebrum,Sub-lobar,Thalamus,Gray Matter,Pulvinar,0 0.077 0.166 8.56 4.65 0.000 1.5 -69 18 5 Right Cerebrum,Occipital Lobe,Precuneus,Gray Matter,Brodmann area 31,1 0.088 0.167 8.45 4.62 0.000 10.5 -48 -6 Right Cerebellum,Anterior Lobe,Culmen,Gray Matter,*,0 0.109 0.167 8.27 4.57 0.000 4.5 -27 -15 6 midbrain (pons near SNr, per Mai atlas) 0.114 0.167 8.23 4.56 0.000 -7.5 -69 51 Left Cerebrum,Parietal Lobe,Precuneus,Gray Matter,Brodmann area 7,2 0.298 0.262 7.43 4.36 0.000 -4.5 -27 -12 midbrain (SNr, per Mai atlas) 0.532 0.303 6.98 4.23 0.000 7.5 -51 18 7 Right Cerebrum,Limbic Lobe,Posterior Cingulate,Gray Matter,Brodmann area 30,1 0.734 0.331 6.66 4.13 0.000 -7.5 -45 18 Left Cerebrum,Limbic Lobe,Posterior Cingulate,Gray Matter,Brodmann area 29,1 0.762 0.349 6.57 4.10 0.000 7.5 -69 51 Right Cerebrum,Parietal Lobe,Precuneus,Gray Matter,Brodmann area 7,1 0.787 0.365 6.49 4.08 0.000 -4.5 -54 -6 Left Cerebellum,Anterior Lobe,Culmen,Gray Matter,*,0 0.810 0.381 6.41 4.05 0.000 -13.5 -66 39 Left Cerebrum,Parietal Lobe,Precuneus,Gray Matter,Brodmann area 7,2 0.881 0.435 6.14 3.97 0.000 -13.5 -72 33 Left Cerebrum,Occipital Lobe,Cuneus,Gray Matter,Brodmann area 7,0 0.910 0.442 6.01 3.92 0.000 -16.5 -45 -3 Left Cerebrum,Occipital Lobe,Lingual Gyrus,Gray Matter,Brodmann area 19,1 0.958 0.509 5.73 3.82 0.000 7.5 -84 12 Right Cerebrum,Occipital Lobe,Cuneus,Gray Matter,Brodmann area 18,0 0.965 0.509 5.67 3.80 0.000 4.5 -30 18 Right Cerebrum,Limbic Lobe,Posterior Cingulate,Gray Matter,Brodmann area 23,4 0.990 0.597 5.34 3.67 0.000 -19.5 -75 51 Left Cerebrum,Parietal Lobe,Precuneus,Gray Matter,Brodmann area 7,2 0.992 0.608 5.29 3.66 0.000 4.5 -78 3 Right Cerebrum,Occipital Lobe,Lingual Gyrus,Gray Matter,Brodmann area 18,0 0.997 0.670 5.09 3.57 0.000 31.5 -69 48 Right Cerebrum,Parietal Lobe,Superior Parietal Lobule,Gray Matter,Brodmann area 7,2 1.000 0.807 4.59 3.36 0.000 31.5 -60 60 Right Cerebrum,Parietal Lobe,Superior Parietal Lobule,Gray Matter,Brodmann area 7,3 1.000 0.871 4.47 3.31 0.000 19.5 -54 15 Right Cerebrum,Limbic Lobe,Posterior Cingulate,Gray Matter,Brodmann area 30,2 1.000 0.977 4.17 3.16 0.001 13.5 -66 0 Right Cerebrum,Occipital Lobe,Lingual Gyrus,Gray Matter,Brodmann area 18,1 2 0.000 0.000 327 0.000 0.000 0.018 14.27 5.62 0.000 7.5 45 9 8 Right Cerebrum,Limbic Lobe,Anterior Cingulate,Gray Matter,Brodmann area 32,0 0.138 0.180 8.06 4.52 0.000 7.5 39 21 Right Cerebrum,Limbic Lobe,Anterior Cingulate,Gray Matter,Brodmann area 32,2 0.332 0.269 7.35 4.34 0.000 7.5 30 33 9 Right Cerebrum,Frontal Lobe,Medial Frontal Gyrus,Gray Matter,Brodmann area 9,0 0.410 0.297 7.18 4.29 0.000 19.5 54 6 Right Cerebrum,Frontal Lobe,Superior Frontal Gyrus,Gray Matter,Brodmann area 10,4 0.552 0.303 6.95 4.22 0.000 -16.5 33 27 Left Cerebrum,Frontal Lobe,Medial Frontal Gyrus,Gray Matter,Brodmann area 9,0 0.563 0.303 6.94 4.22 0.000 -10.5 42 9 Left Cerebrum,Limbic Lobe,Anterior Cingulate,Gray Matter,Brodmann area 32,1 0.851 0.424 6.26 4.01 0.000 -4.5 45 0 Left Cerebrum,Limbic Lobe,Anterior Cingulate,Gray Matter,Brodmann area 32,0 0.999 0.745 4.94 3.51 0.000 -4.5 45 -12 10 Left Cerebrum,Frontal Lobe,Medial Frontal Gyrus,Gray Matter,Brodmann area 11,0 1.000 0.790 4.74 3.43 0.000 -19.5 51 15 Left Cerebrum,Frontal Lobe,Superior Frontal Gyrus,Gray Matter,Brodmann area 10,3 1.000 0.888 4.43 3.29 0.001 4.5 36 -3 Right Cerebrum,Limbic Lobe,Anterior Cingulate,Gray Matter,Brodmann area 32,0 3 0.000 0.000 263 0.000 0.026 0.111 9.59 4.87 0.000 -19.5 12 33 11 Left Cerebrum,Limbic Lobe,Cingulate Gyrus,Gray Matter,Brodmann area 32,3 0.068 0.164 8.68 4.67 0.000 -28.5 21 39 12 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 8,1 0.649 0.315 6.83 4.19 0.000 -49.5 24 18 Left Cerebrum,Frontal Lobe,Inferior Frontal Gyrus,Gray Matter,Brodmann area 45,0 0.697 0.318 6.77 4.17 0.000 -49.5 33 9 Left Cerebrum,Frontal Lobe,Inferior Frontal Gyrus,Gray Matter,Brodmann area 46,3 0.864 0.433 6.21 3.99 0.000 -46.5 21 30 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 9,1 0.986 0.569 5.42 3.71 0.000 -49.5 18 9 Left Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 44,0 0.996 0.670 5.14 3.60 0.000 -34.5 27 12 Left Cerebrum,Frontal Lobe,Inferior Frontal Gyrus,Gray Matter,Brodmann area 13,5 1.000 0.910 4.29 3.22 0.001 -28.5 33 9 No Gray Matter found,,,,, Decreased rCBF with 60mg bid SYN115 See legend at bottom of table.

cluster-level voxel-level atlas location

pFWE-corr qFDR-corr kE puncorr pFWE-corr qFDR-corr T Zequiv puncorr Xmm Ymm Zmm cluster # VOI Nearest gray matter according to Talairach Daemon (last number = distance in mm) 4 0.000 0.000 235 0.000 0.204 0.223 7.74 4.44 0.000 -46.5 6 51 13 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 6,0 0.281 0.262 7.48 4.37 0.000 -22.5 -12 54 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 6,1 0.882 0.435 6.14 3.97 0.000 -40.5 -18 66 Left Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 6,4 0.891 0.435 6.10 3.95 0.000 -25.5 3 57 Left Cerebrum,Frontal Lobe,Sub-Gyral,Gray Matter,Brodmann area 6,1 0.956 0.509 5.74 3.83 0.000 -10.5 12 54 Left Cerebrum,Frontal Lobe,Superior Frontal Gyrus,Gray Matter,Brodmann area 6,2 0.957 0.509 5.74 3.82 0.000 -25.5 -9 42 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 6,1 0.998 0.705 5.01 3.54 0.000 -10.5 0 57 Left Cerebrum,Frontal Lobe,Medial Frontal Gyrus,Gray Matter,Brodmann area 6,2 1.000 0.790 4.73 3.42 0.000 -34.5 3 45 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 6,3 1.000 0.807 4.57 3.35 0.000 -31.5 -3 39 Left Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 6,3 1.000 0.887 4.45 3.30 0.000 -31.5 -24 63 Left Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 4,0 5 0.000 0.000 75 0.000 0.660 0.315 6.81 4.18 0.000 34.5 -36 60 14 Right Cerebrum,Parietal Lobe,Postcentral Gyrus,Gray Matter,Brodmann area 2,0 0.956 0.509 5.74 3.83 0.000 25.5 -27 69 Right Cerebrum,Parietal Lobe,Postcentral Gyrus,Gray Matter,Brodmann area 3,3 6 0.000 0.000 75 0.000 0.718 0.326 6.71 4.15 0.000 -28.5 -60 63 15 Left Cerebrum,Parietal Lobe,Superior Parietal Lobule,Gray Matter,Brodmann area 7,3 0.987 0.569 5.40 3.70 0.000 -37.5 -63 48 Left Cerebrum,Parietal Lobe,Superior Parietal Lobule,Gray Matter,Brodmann area 7,0 1.000 0.807 4.61 3.37 0.000 -16.5 -54 54 Left Cerebrum,Parietal Lobe,Precuneus,Gray Matter,Brodmann area 7,1 1.000 0.829 4.53 3.33 0.000 -31.5 -69 45 Left Cerebrum,Parietal Lobe,Superior Parietal Lobule,Gray Matter,Brodmann area 7,1 7 0.780 0.264 8 0.088 0.906 0.442 6.03 3.93 0.000 -34.5 -87 6 Left Cerebrum,Occipital Lobe,Middle Occipital Gyrus,Gray Matter,Brodmann area 19,0 8 0.992 0.514 3 0.283 0.940 0.506 5.85 3.86 0.000 28.5 21 57 Right Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 6,0 9 0.992 0.514 3 0.283 0.959 0.509 5.72 3.82 0.000 -34.5 -45 -9 Left Cerebrum,Occipital Lobe,Fusiform Gyrus,Gray Matter,Brodmann area 37,0 10 0.946 0.406 5 0.169 0.960 0.509 5.71 3.82 0.000 -13.5 -78 12 16 Left Cerebrum,Occipital Lobe,Cuneus,Gray Matter,Brodmann area 17,0 11 0.845 0.309 7 0.108 0.963 0.509 5.69 3.81 0.000 -13.5 -51 9 Left Cerebrum,Limbic Lobe,Posterior Cingulate,Gray Matter,Brodmann area 30,0 12 0.396 0.176 14 0.029 0.966 0.509 5.66 3.80 0.000 25.5 -9 54 Right Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 6,0 13 0.641 0.223 10 0.060 0.972 0.525 5.61 3.78 0.000 -7.5 18 36 Left Cerebrum,Limbic Lobe,Cingulate Gyrus,Gray Matter,Brodmann area 32,2 1.000 0.807 4.62 3.37 0.000 -7.5 15 45 Left Cerebrum,Frontal Lobe,Medial Frontal Gyrus,Gray Matter,Brodmann area 6,2 14 0.509 0.212 12 0.041 0.977 0.539 5.55 3.76 0.000 37.5 -33 -9 17 Right Cerebrum,Limbic Lobe,Parahippocampal Gyrus,Gray Matter,Brodmann area 36,2 1.000 0.910 4.35 3.25 0.001 37.5 -18 -15 Right Cerebrum,Temporal Lobe,Sub-Gyral,Gray Matter,Brodmann area 20,4 15 0.020 0.010 37 0.001 0.984 0.568 5.45 3.72 0.000 13.5 -15 63 18 Right Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 6,2 1.000 0.915 4.27 3.21 0.001 13.5 -12 51 Right Cerebrum,Frontal Lobe,Medial Frontal Gyrus,Gray Matter,Brodmann area 6,0 16 0.203 0.088 19 0.013 0.986 0.569 5.42 3.71 0.000 25.5 24 36 Right Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 8,2 17 0.992 0.514 3 0.283 0.992 0.608 5.30 3.66 0.000 4.5 -30 63 Right Cerebrum,Frontal Lobe,Paracentral Lobule,Gray Matter,Brodmann area 6,0 18 0.901 0.367 6 0.134 0.997 0.670 5.13 3.59 0.000 7.5 24 51 Right Cerebrum,Frontal Lobe,Superior Frontal Gyrus,Gray Matter,Brodmann area 6,2 19 0.573 0.212 11 0.0495 0.997 0.670 5.11 3.58 0.000 40.5 -9 -18 19 Right Cerebrum,Temporal Lobe,Sub-Gyral,Gray Matter,Brodmann area 20,2 20 0.641 0.223 10 0.060 0.997 0.670 5.10 3.58 0.000 22.5 15 30 Right Cerebrum,Limbic Lobe,Cingulate Gyrus,Gray Matter,Brodmann area 32,4 1.000 0.790 4.70 3.41 0.000 22.5 6 30 Right Cerebrum,Limbic Lobe,Cingulate Gyrus,Gray Matter,Brodmann area 32,5 21 0.999 0.545 2 0.381 0.999 0.756 4.90 3.50 0.000 25.5 -24 -15 Right Cerebrum,Limbic Lobe,Parahippocampal Gyrus,Gray Matter,Brodmann area 35,1 22 0.104 0.048 24 0.006 0.999 0.756 4.90 3.50 0.000 22.5 39 24 Right Cerebrum,Frontal Lobe,Medial Frontal Gyrus,Gray Matter,Brodmann area 9,2 23 0.711 0.228 9 0.072 0.999 0.773 4.87 3.48 0.000 -31.5 42 3 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 10,5 24 1.000 0.545 1 0.545 1.000 0.790 4.80 3.46 0.000 7.5 -30 54 Right Cerebrum,Frontal Lobe,Paracentral Lobule,Gray Matter,Brodmann area 6,0 25 0.711 0.228 9 0.072 1.000 0.790 4.75 3.43 0.000 37.5 -42 33 Right Cerebrum,Parietal Lobe,Supramarginal Gyrus,Gray Matter,Brodmann area 40,1 1.000 0.807 4.61 3.37 0.000 34.5 -48 27 Right Cerebrum,Temporal Lobe,Superior Temporal Gyrus,Gray Matter,Brodmann area 39,5 26 0.711 0.228 9 0.072 1.000 0.790 4.74 3.43 0.000 37.5 -72 6 Right Cerebrum,Occipital Lobe,Middle Occipital Gyrus,Gray Matter,Brodmann area 19,3 27 0.573 0.212 11 0.0495 1.000 0.790 4.73 3.42 0.000 16.5 15 3 20 Right Cerebrum,Sub-lobar,Caudate,Gray Matter,Caudate Head,1 28 0.573 0.212 11 0.0495 1.000 0.790 4.71 3.42 0.000 28.5 -30 45 Right Cerebrum,Parietal Lobe,Postcentral Gyrus,Gray Matter,Brodmann area 3,3 29 0.976 0.463 4 0.216 1.000 0.807 4.59 3.36 0.000 -31.5 6 6 Left Cerebrum,Sub-lobar,Claustrum,Gray Matter,*,1 30 0.992 0.514 3 0.283 1.000 0.888 4.43 3.29 0.001 -28.5 24 -6 Left Cerebrum,Frontal Lobe,Inferior Frontal Gyrus,Gray Matter,Brodmann area 47,3 31 0.976 0.463 4 0.216 1.000 0.896 4.41 3.28 0.001 -22.5 15 6 Left Cerebrum,Sub-lobar,Lentiform Nucleus,Gray Matter,Putamen,1 Decreased rCBF with 60mg bid SYN115 See legend at bottom of table.

cluster-level voxel-level atlas location

pFWE-corr qFDR-corr kE puncorr pFWE-corr qFDR-corr T Zequiv puncorr Xmm Ymm Zmm cluster # VOI Nearest gray matter according to Talairach Daemon (last number = distance in mm) 32 0.946 0.406 5 0.169 1.000 0.910 4.38 3.26 0.001 7.5 9 42 Right Cerebrum,Limbic Lobe,Cingulate Gyrus,Gray Matter,Brodmann area 32,0 33 1.000 0.545 1 0.545 1.000 0.910 4.36 3.25 0.001 -61.5 -6 -12 Left Cerebrum,Temporal Lobe,Middle Temporal Gyrus,Gray Matter,Brodmann area 21,0 34 1.000 0.545 1 0.545 1.000 0.910 4.34 3.24 0.001 -4.5 0 -6 Left Cerebrum,Sub-lobar,*,Gray Matter,Hypothalamus,2 35 0.999 0.545 2 0.381 1.000 0.910 4.33 3.24 0.001 34.5 -75 24 Right Cerebrum,Occipital Lobe,Superior Occipital Gyrus,Gray Matter,Brodmann area 19,2 36 0.999 0.545 2 0.381 1.000 0.910 4.32 3.23 0.001 22.5 -57 18 Right Cerebrum,Limbic Lobe,Posterior Cingulate,Gray Matter,Brodmann area 30,5 37 0.976 0.463 4 0.216 1.000 0.910 4.31 3.23 0.001 -46.5 3 33 Left Cerebrum,Frontal Lobe,Inferior Frontal Gyrus,Gray Matter,Brodmann area 9,0 38 0.999 0.545 2 0.381 1.000 0.910 4.31 3.23 0.001 46.5 -45 27 Right Cerebrum,Parietal Lobe,Inferior Parietal Lobule,Gray Matter,Brodmann area 40,4 39 1.000 0.545 1 0.545 1.000 0.910 4.30 3.23 0.001 55.5 -60 0 Right Cerebrum,Temporal Lobe,Middle Temporal Gyrus,Gray Matter,Brodmann area 37,1 40 0.992 0.514 3 0.283 1.000 0.910 4.29 3.22 0.001 37.5 -9 36 Right Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 6,2 41 0.946 0.406 5 0.169 1.000 0.910 4.29 3.22 0.001 -7.5 36 36 Left Cerebrum,Frontal Lobe,Medial Frontal Gyrus,Gray Matter,Brodmann area 8,2 42 1.000 0.545 1 0.545 1.000 0.928 4.25 3.20 0.001 -46.5 -9 42 Left Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 4,1 43 0.999 0.545 2 0.381 1.000 0.958 4.20 3.18 0.001 -7.5 48 33 Left Cerebrum,Frontal Lobe,Superior Frontal Gyrus,Gray Matter,Brodmann area 9,3 44 1.000 0.545 1 0.545 1.000 0.968 4.19 3.17 0.001 -58.5 -9 -9 Left Cerebrum,Temporal Lobe,Middle Temporal Gyrus,Gray Matter,Brodmann area 21,3 45 1.000 0.545 1 0.545 1.000 0.986 4.15 3.15 0.001 -43.5 3 21 Left Cerebrum,Frontal Lobe,Inferior Frontal Gyrus,Gray Matter,Brodmann area 9,3 46 1.000 0.545 1 0.545 1.000 0.986 4.14 3.15 0.001 -22.5 15 54 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 6,0 47 1.000 0.545 1 0.545 1.000 0.998 4.10 3.13 0.001 43.5 -27 66 Right Cerebrum,Parietal Lobe,Postcentral Gyrus,Gray Matter,Brodmann area 3,4 48 1.000 0.545 1 0.545 1.000 0.998 4.10 3.13 0.001 -16.5 6 45 Left Cerebrum,Limbic Lobe,Cingulate Gyrus,Gray Matter,Brodmann area 24,1 49 1.000 0.545 1 0.545 1.000 0.998 4.09 3.13 0.001 -16.5 -36 54 Left Cerebrum,Frontal Lobe,Paracentral Lobule,Gray Matter,Brodmann area 3,0 50 1.000 0.545 1 0.545 1.000 0.998 4.09 3.12 0.001 -22.5 -69 18 Left Cerebrum,Occipital Lobe,Cuneus,Gray Matter,Brodmann area 18,1 51 1.000 0.545 1 0.545 1.000 0.998 4.08 3.12 0.001 13.5 -63 66 Right Cerebrum,Parietal Lobe,Superior Parietal Lobule,Gray Matter,Brodmann area 7,4 52 1.000 0.545 1 0.545 1.000 0.998 4.08 3.12 0.001 -37.5 0 57 Left Cerebrum,Frontal Lobe,Middle Frontal Gyrus,Gray Matter,Brodmann area 6,0 53 1.000 0.545 1 0.545 1.000 0.998 4.05 3.10 0.001 -34.5 -12 36 Left Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 6,3 54 1.000 0.545 1 0.545 1.000 0.998 4.05 3.10 0.001 -16.5 -72 15 Left Cerebrum,Occipital Lobe,Cuneus,Gray Matter,Brodmann area 18,2 55 1.000 0.545 1 0.545 1.000 0.998 4.05 3.10 0.001 10.5 -6 45 Right Cerebrum,Limbic Lobe,Cingulate Gyrus,Gray Matter,Brodmann area 24,0 56 1.000 0.545 1 0.545 1.000 0.998 4.04 3.10 0.001 34.5 -24 57 Right Cerebrum,Frontal Lobe,Precentral Gyrus,Gray Matter,Brodmann area 4,1 57 1.000 0.545 1 0.545 1.000 0.998 4.04 3.10 0.001 31.5 -87 36 Right Cerebrum,Occipital Lobe,Cuneus,Gray Matter,Brodmann area 19,2 58 1.000 0.545 1 0.545 1.000 0.998 4.04 3.10 0.001 -28.5 30 18 No Gray Matter found,,,,, 59 1.000 0.545 1 0.545 1.000 0.998 4.03 3.10 0.001 -13.5 -30 30 No Gray Matter found,,,,, 60 1.000 0.545 1 0.545 1.000 0.998 4.03 3.09 0.001 -16.5 -39 45 Left Cerebrum,Frontal Lobe,Paracentral Lobule,Gray Matter,Brodmann area 5,3

LEGEND: Complete output from SPM analysis of regional decreases with SPM115 60mg p.o. b.i.d. vs. placebo. Highlighted p values indicate clusters that would be considered significant at p<0.05 or p<0.10 by the statistical method given in the column heading. The pre-specified statistical analysis method was cluster false discovery rate (FDR) < 0.05 (third column, to the left of the column titled kE). WM = white matter. Supplementary Table 4. Prior probabilities used for the Bayesian pharmacodynamic parameter estimation.

Parameter Prior probability distribution

EC50 constant and positive between 200 and 5000 ng/ml, and zero elsewhere

Emax a Gaussian curve with mean 0, standard deviation (SD) 30%; zero outside

the interval *−100%, 0+ (since we know the effect was a decrease) n a Gaussian curve with mean 1, SD 10; zero outside the interval [0.5, 25]

E(0) SYN115 only: 0

SYN115+levodopa: a Gaussian curve with mean zero and SD = 30, but

zero outside the interval *−100%, +100%+ model equal probability for either model

100 150 200 250 300 350 400 50 0

p [13.5, −42, −3] Extent thresholdk=20voxels Height thresholdT=2.131847{p<0.05(unc.)} SPMresults: 11 c 0.1 1.000 1.000 1.000 1.000 1.000 1.000 1.000 p 0.004 0.000 0.000 0.001 < < FWE−corr p−values adjustedforsearchvolume ./blackf/syn/spm/spm17a 0.2 cluster−level 0.872 0.872 0.872 0.872 0.872 0.872 0.872 q 0.001 0.000 0.000 0.000 table shows3localmaximamorethan8.0mmapart FDR−corr 0.3 20 66 22 37 53 28 85 651 1076 988 774 k E 0.4 0.363 0.106 0.340 0.218 0.144 0.282 0.070 p 0.000 0.000 0.000 0.000 SPM{T uncorr 0.5 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.223 1.000 1.000 1.000 1.000 1.000 p Voxel size:3.0mm mmmm;(resel=47.12voxels) Volume: 1231065=45595 voxels=867.9resels FWHM =10.511.410.6mm mmmm;3.53.8{voxels} Degrees offreedom=[1.0, 4.0] FWE−corr < 4 } 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 q 0.6 FDR−corr peak−level 2.78 5.47 2.54 3.76 3.24 4.75 5.90 4.31 3.15 3.26 4.17 6.09 4.87 6.30 6.47 7.11 10.88 7.91 11.80 11.54 27.93 12.23 13.21 6.94 15.71 12.88

T 1 5 4 3 2 1 0.5 0.7 1.97 2.78 1.86 2.33 2.15 2.61 2.87 2.50 2.12 2.16 2.46 2.90 2.64 2.94 2.97 3.08 3.54 3.20 3.62 3.60 4.42 3.66 3.73 3.05 3.90 3.71 ( Z Design matrix ≡ ) contrast(s) 0.8 p 1 0.025 0.003 0.031 0.010 0.016 0.004 0.002 0.006 0.017 0.015 0.007 0.002 0.004 0.002 0.001 0.001 0.000 0.001 0.000 0.000 0.000 0.000 0.000 0.001 0.000 0.000 uncorr 0.9 −52 −1248 1412−18 −34 1536 40−6621 −56 −342 −4633 215−15 −20 −729 14−4842 −34 2430 −46 048 −812−15 −14 −7812 −845−9 14−42−3 −28 −639 445−6 −58 −2718 105412 −34 27−9 58−1233 −34 −90 46−2412 10−7536 mm 62−5130 8−600 1.5 1 100 150 200 250 300 350 400 50 0

0 SPMmip CBF decreaseswithSYN115(5re−enrollers,bothdoses) FWEp: 40.628,FDRp:Inf, FWEc: 651,FDRc:651 Expected numberofclusters, =43.94 Expected voxelspercluster, =26.116 Extent threshold:k=20voxels, p=0.363(1.000) Height threshold:T=2.13, p=0.049(1.000) Statistics: [13.5, −42, −3] Extent thresholdk=20voxels Height thresholdT=2.131847{p<0.05(unc.)} SPMresults: 0.1 0.000 p < < FWE−corr p−values adjustedforsearchvolume ./blackf/syn/spm/spm17a 0.2 cluster−level table shows320localmaximamorethan8.0mmapart 0.000 q FDR−corr 0.3 1076 k E 0.4 0.000 p SPM{T uncorr 0.5 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.223 1.000 1.000 1.000 p Voxel size:3.0mm mmmm;(resel=47.12voxels) Volume: 1231065=45595 voxels=867.9resels FWHM =10.511.410.6mm mmmm;3.53.8{voxels} Degrees offreedom=[1.0, 4.0] FWE−corr < 4 } 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 q 0.6 FDR−corr peak−level 2.33 2.65 2.87 2.94 3.12 3.17 3.20 3.24 3.29 3.64 3.96 3.97 4.18 4.51 4.80 4.81 5.46 5.81 6.00 6.75 27.93 6.92 6.94 12.88

T 1 5 4 3 2 1 0.5 0.7 1.76 1.91 2.00 2.03 2.11 2.13 2.14 2.15 2.17 2.29 2.40 2.40 2.46 2.55 2.63 2.63 2.78 2.85 2.89 3.02 4.42 3.05 3.05 3.71 ( Z Design matrix ≡ ) contrast(s) 0.8 p 1 0.039 0.028 0.023 0.021 0.018 0.017 0.016 0.016 0.015 0.011 0.008 0.008 0.007 0.005 0.004 0.004 0.003 0.002 0.002 0.001 0.000 0.001 0.001 0.000 uncorr 0.9 8−753 −8−54−6 22−6618 −2−8148 −8−7854 4−4815 −14 −45−9 20−6633 28−36−9 16−18 8−36−12 −4−303 8−180 −2−249 2−7527 4−6018 8−18−12 4−8439 8−219 14−42−3 −8−30−9 14−7521 10−7536 mm 8−600 1.5 1 100 150 200 250 300 350 400 50 0

0 SPMmip CBF decreaseswithSYN115(5re−enrollers,bothdoses) FWEp: 40.628,FDRp:Inf, FWEc: 651,FDRc:651 Expected numberofclusters, =43.94 Expected voxelspercluster, =26.116 Extent threshold:k=20voxels, p=0.363(1.000) Height threshold:T=2.13, p=0.049(1.000) Statistics: [61.5, −51, 30] Extent thresholdk=20voxels Height thresholdT=2.131847{p<0.05(unc.)} SPMresults: 0.1 < < 0.001 p FWE−corr p−values adjustedforsearchvolume ./blackf/syn/spm/spm17a 0.2 cluster−level table shows320localmaximamorethan8.0mmapart 0.000 q FDR−corr 0.3 774 k E 0.4 0.000 p SPM{T uncorr 0.5 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 p Page 1 Voxel size:3.0mm mmmm;(resel=47.12voxels) Volume: 1231065=45595 voxels=867.9resels FWHM =10.511.410.6mm mmmm;3.53.8{voxels} Degrees offreedom=[1.0, 4.0] FWE−corr 4 } 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 q 0.6 < FDR−corr peak−level 3.07 3.21 3.36 3.49 3.59 3.61 3.84 3.93 3.99 4.08 4.18 4.24 4.79 4.92 5.02 5.21 5.30 5.32 5.56 5.58 6.22 6.54 7.15 7.22 9.51 15.71 10.24 11.54 13.21

T 1 5 4 3 2 1 0.5 0.7 2.09 2.14 2.19 2.24 2.28 2.28 2.36 2.39 2.40 2.43 2.46 2.48 2.62 2.66 2.68 2.72 2.74 2.75 2.80 2.80 2.93 2.99 3.09 3.10 3.40 3.90 3.47 3.60 3.73 ( Z Design matrix ≡ ) contrast(s) 0.8 p 1 0.018 0.016 0.014 0.013 0.011 0.011 0.009 0.008 0.008 0.007 0.007 0.007 0.004 0.004 0.004 0.003 0.003 0.003 0.003 0.003 0.002 0.001 0.001 0.001 0.000 0.000 0.000 0.000 0.000 uncorr 0.9 46−429 52−642 64−618 58−3315 38−90 62−429 68−486 2824−15 283 52−1218 34240 4024−9 62−4230 5027−9 2818−3 58−156 2615−12 40−3012 44−2733 68−159 46−3927 56−333 64−306 56−240 62−5130 2018−18 169−3 58−1233 mm 46−2412 1.5 1 100 150 200 250 300 350 400 50 0

T 1 5 4 3 2 1 0.5 0.7 1.81 1.89 1.94 1.98 1.98 2.08 ( Z Design matrix ≡ ) contrast(s) 0.8 p 1 0.035 0.029 0.026 0.024 0.024 0.019 uncorr 0.9 38−2127 34−2721 46−615 44321 32−99 56−18−6 mm 1.5 1 100 150 200 250 300 350 400 50 0

0 SPMmip CBF decreaseswithSYN115(5re−enrollers,bothdoses) FWEp: 40.628,FDRp:Inf, FWEc: 651,FDRc:651 Expected numberofclusters, =43.94 Expected voxelspercluster, =26.116 Extent threshold:k=20voxels, p=0.363(1.000) Height threshold:T=2.13, p=0.049(1.000) Statistics: [−34.5, −9, 0] Extent thresholdk=20voxels Height thresholdT=2.131847{p<0.05(unc.)} SPMresults: 0.1 0.000 p FWE−corr p−values adjustedforsearchvolume ./blackf/syn/spm/spm17a 0.2 < < cluster−level table shows320localmaximamorethan8.0mmapart 0.000 q FDR−corr 0.3 988 k E 0.4 0.000 p SPM{T uncorr < 0.5 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 p Voxel size:3.0mm mmmm;(resel=47.12voxels) Volume: 1231065=45595 voxels=867.9resels FWHM =10.511.410.6mm mmmm;3.53.8{voxels} Degrees offreedom=[1.0, 4.0] FWE−corr 4 } 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 q 0.6 FDR−corr peak−level 2.32 3.14 3.27 3.51 3.65 3.82 3.88 3.89 3.89 3.90 4.09 4.18 4.31 4.42 4.91 5.10 5.32 6.19 6.25 7.39 7.39 8.45 9.41 9.62 12.23 10.48 10.88 11.80

T 1 5 4 3 2 1 0.5 0.7 1.76 2.11 2.16 2.25 2.30 2.35 2.37 2.37 2.37 2.38 2.43 2.46 2.50 2.53 2.65 2.70 2.75 2.92 2.93 3.12 3.12 3.27 3.39 3.41 3.66 3.50 3.54 3.62 ( Z Design matrix ≡ ) contrast(s) 0.8 p 1 0.040 0.017 0.015 0.012 0.011 0.009 0.009 0.009 0.009 0.009 0.007 0.007 0.006 0.006 0.004 0.003 0.003 0.002 0.002 0.001 0.001 0.001 0.000 0.000 0.000 0.000 0.000 0.000 uncorr 0.9 −46 33−15 −56 12−3 −58 033 −44 18−15 −58 −3945 −64 −213 −62 −3042 −44 −3921 −40 −5715 −50 −4545 −20 9 −14 315 −64 −4227 −40 −3021 −62 −120 −58 −5418 −68 −3321 −58 −1818 −40 30 −28 3−3 −62 39 −52 12−15 −44 −5124 −34 −90 −40 18−6 −46 −1815 −58 −2718 mm −34 27−9 1.5 1 100 150 200 250 300 350 400 50 0

0 SPMmip CBF decreaseswithSYN115(5re−enrollers,bothdoses) FWEp: 40.628,FDRp:Inf, FWEc: 651,FDRc:651 Expected numberofclusters, =43.94 Expected voxelspercluster, =26.116 Extent threshold:k=20voxels, p=0.363(1.000) Height threshold:T=2.13, p=0.049(1.000) Statistics: [10.5, 54, 12] Extent thresholdk=20voxels Height thresholdT=2.131847{p<0.05(unc.)} SPMresults: 0.1 0.004 p FWE−corr p−values adjustedforsearchvolume ./blackf/syn/spm/spm17a 0.2 cluster−level table shows320localmaximamorethan8.0mmapart 0.001 q FDR−corr 0.3 < < 651 k E 0.4 0.000 p SPM{T uncorr 0.5 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 p Voxel size:3.0mm mmmm;(resel=47.12voxels) Volume: 1231065=45595 voxels=867.9resels FWHM =10.511.410.6mm mmmm;3.53.8{voxels} Degrees offreedom=[1.0, 4.0] FWE−corr < 4 } 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 1.084 q 0.6 FDR−corr peak−level 2.62 2.67 2.74 2.79 2.87 2.91 3.50 3.59 3.60 3.81 3.82 3.90 4.02 4.03 4.23 5.13 5.30 6.05 7.91 6.15 6.30 7.11

T 1 5 4 3 2 1 0.5 0.7 1.90 1.92 1.95 1.97 2.00 2.02 2.25 2.28 2.28 2.35 2.35 2.38 2.41 2.42 2.48 2.71 2.74 2.90 3.20 2.92 2.94 3.08 ( Z Design matrix ≡ ) contrast(s) 0.8 p 1 0.029 0.028 0.026 0.024 0.023 0.022 0.012 0.011 0.011 0.009 0.009 0.009 0.008 0.008 0.007 0.003 0.003 0.002 0.001 0.002 0.002 0.001 uncorr 0.9 8−645 201527 −4360 103615 −14 480 203618 −28 42−3 10939 103927 −836−9 −34 513 102721 −20 4521 81527 −254−15 34456 28366 105412 −26 549 −22 42−12 −845−9 mm 445−6 1.5 1 100 150 200 250 300 350 400 50 0

p [7.5, 9, 45] Extent thresholdk=10voxels Height thresholdT=3.686155{p<0.001(unc.)} SPMresults: 7 c 0.1 CBF decreasewithSYN115(bothdoses) p 0.000 0.186 0.001 0.016 0.211 0.000 0.548 FWE−corr p−values adjustedforsearchvolume ./blackf/syn/spm/spm20 0.2 cluster−level < < q 0.000 0.093 0.001 0.010 0.093 0.000 0.268 table shows3localmaximamorethan8.0mmapart FDR−corr 0.3 98 21 74 42 20 827 12 k E 0.4 p 0.000 0.013 0.000 0.001 0.015 0.000 0.051 SPM{T uncorr 0.5 0.932 0.172 0.011 1.000 0.498 0.488 0.130 0.788 0.997 1.000 0.812 0.034 0.682 p 0.883 Voxel size:3.0mm mmmm;(resel=42.27voxels) Volume: 1229931=45553 voxels=966.2resels FWHM =10.211.0mm mmmm;3.43.7{voxels} Degrees offreedom=[1.0, 16.0] FWE−corr < 16 } 0.434 0.322 0.163 0.979 0.322 0.322 0.322 0.432 0.712 0.844 0.432 0.200 0.399 q 0.432 0.6 FDR−corr peak−level 4.94 6.48 8.11 3.80 5.89 5.92 6.64 5.32 4.41 4.06 5.27 7.40 5.54 5.10 20 15 10

T 1 5 0.7 1 3.80 4.48 5.04 3.16 4.24 4.25 4.54 3.98 3.52 3.32 3.96 4.81 4.08 3.87 ( Z Design matrix ≡ 2 ) contrast(s) 0.8 p 3 0.000 0.000 0.000 0.001 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 uncorr 4 0.9 8945 14−366 2−7512 −26 054 −38 −3012 8−189 −10 −45−9 10654 mm −10 1251 −26 −957 −50 −5121 −2−7233 81848 −32 −363 5 1 100 150 200 250 300 350 400 50 0

0 SPMmip FWEp: 7.179,FDRp:Inf,FWEc: 42,FDRc:42 Expected numberofclusters, =1.12 Expected voxelspercluster, =3.096 Extent threshold:k=10voxels, p=0.071(0.673) Height threshold:T=3.69, p=0.001(1.000) Statistics: [7.5, 9, 45] Extent thresholdk=10voxels Height thresholdT=3.686155{p<0.001(unc.)} SPMresults: 0.1 CBF decreasewithSYN115(bothdoses) 0.000 p FWE−corr p−values adjustedforsearchvolume ./blackf/syn/spm/spm20 0.2 cluster−level < < table shows320localmaximamorethan8.0mmapart 0.000 q FDR−corr 0.3 98 k E 0.4 0.000 p SPM{T uncorr 0.5 0.998 0.011 0.924 0.788 0.682 p Voxel size:3.0mm mmmm;(resel=42.27voxels) Volume: 1229931=45553 voxels=966.2resels FWHM =10.211.0mm mmmm;3.43.7{voxels} Degrees offreedom=[1.0, 16.0] FWE−corr < 16 } 0.712 0.163 0.432 0.432 0.399 q 0.6 FDR−corr peak−level 4.34 8.11 4.97 5.32 5.54 20 15 10

T 1 5 0.7 1 3.48 5.04 3.81 3.98 4.08 ( Z Design matrix ≡ 2 ) contrast(s) 0.8 p 3 0.000 0.000 0.000 0.000 0.000 uncorr 4 0.9 8945 10−648 10−957 10654 mm 81848 5 1 100 150 200 250 300 350 400 50 0

0 SPMmip FWEp: 7.179,FDRp:Inf,FWEc: 42,FDRc:42 Expected numberofclusters, =1.12 Expected voxelspercluster, =3.096 Extent threshold:k=10voxels, p=0.071(0.673) Height threshold:T=3.69, p=0.001(1.000) Statistics: [−1.5, −72, 33] Extent thresholdk=10voxels Height thresholdT=3.686155{p<0.001(unc.)} SPMresults: 0.1 < < CBF decreasewithSYN115(bothdoses) 0.000 p FWE−corr p−values adjustedforsearchvolume ./blackf/syn/spm/spm20 0.2 cluster−level table shows320localmaximamorethan8.0mmapart 0.000 q FDR−corr 0.3 827 k E 0.4 0.000 p SPM{T uncorr 0.5 0.999 0.998 0.996 0.995 0.986 0.983 0.920 0.919 0.906 0.864 0.825 0.756 0.632 0.599 0.509 0.410 0.034 0.283 0.172 0.130 p < Voxel size:3.0mm mmmm;(resel=42.27voxels) Volume: 1229931=45553 voxels=966.2resels FWHM =10.211.0mm mmmm;3.43.7{voxels} Degrees offreedom=[1.0, 16.0] FWE−corr 16 } 0.723 0.712 0.712 0.702 0.601 0.599 0.432 0.432 0.432 0.432 0.432 0.425 0.378 0.377 0.322 0.322 0.200 0.322 0.322 0.322 q 0.6 FDR−corr peak−level 4.27 4.36 4.42 4.47 4.62 4.65 4.98 4.99 5.03 5.15 5.24 5.39 5.63 5.69 5.87 6.01 7.40 6.21 6.48 6.64 20 15 10

T 1 5 0.7 1 3.44 3.49 3.52 3.55 3.63 3.64 3.82 3.82 3.84 3.90 3.94 4.01 4.12 4.15 4.23 4.29 4.81 4.37 4.48 4.54 ( Z Design matrix ≡ 2 ) contrast(s) 0.8 p 3 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 uncorr 4 0.9 8−51−6 10−633 10−5112 −20 −7224 −8−846 −20 −36−12 10−7218 4−6018 10−6636 −8−549 −14 −7512 −10 −639 −4−300 20−39−9 −2−42−9 −2−7233 −8−219 4−27−15 2−7512 mm −10 −45−9 5 1 SUPPLEMENTARY TABLE 6 Page 4

The foregoing Table shows results from an SPM analysis using data from all subjects, in which responses to any dose of drug are weighted similarly to avoid the potential bias that might result from selecting VOIs from the 60mg-vs-placebo group only.

Voxels with p<0.001 (uncorrected) are shown in the color figures at right. Broadly, the results were similar to our primary analysis. As listed on the preceding pages, four clusters of voxels were found with significantly decreased rCBF: medial prefrontal cortex; cuneus/precuneus, bilateral midbrain, and left thalamus; right thalamus; and left superior frontal gyrus. Most of the peaks in these clusters are at or near peaks found in our primary analysis (drug vs placebo in 60mg group). However, to address the reviewer’s concern further, we selected two voxels from this new analysis that are peaks for significant clusters, but were not chosen for Table 2 in the primary analysis. Note that both were in regions previously identified (in fact, each was only 1 voxel from a peak listed in Supplementary Table 3). The points are (7.5, 9, 45), in medial frontal gyrus, BA 32, and (−10.5, 12, 51), in superior frontal gyrus, BA 6. At VOIs centered on these points, the 60mg dose group’s rCBF decrease did not differ significantly from that of the 20mg dose group (see the 2 graphs below).

regional CBF (scaled) regional CBF (scaled) all ASL scans all ASL scans 0% 0% medial frontal superior frontal -2% -2% gyrus, BA32 gyrus, BA6

-4% -4%

-6% -6%

-8% -8% % change% fromplacebo % change% fromplacebo -10% -10%

-12% -12% placebo 20 mg bid 60 mg bid placebo 20 mg bid 60 mg bid

Finally, using SPM8, we directly searched for points with a larger response in the 20mg group than in the 60mg group, and there were no significant clusters. Supplementary Table 7. Expected effects in the indirect pathway of giving an A2a antagonist (compare Figure 4). References cited in the footnotes are listed below the footnotes.

Receptor on Corresponding the cell body Expected change in Axon termini Transmitter Brain region or dendrites firing rate metabolism are located released at of cells in of cell and blood flow in: axon termini this region at axon termini Striatum and A2a (and D2) Decreased * Decreased † GPe / VP GABA ** ventral striatum GABAA GPe / VP Increased Increased ¶ STN GABA (inhibitory) GABA Subthalamic n. Decreased Decreased GPi Glutamate (inhibitory) Glutamate GPi Decreased Decreased ‡ Thalamus GABA (excitatory) GABA Thalamus Increased Increased § Cortex Glutamate (inhibitory) Glutamate Cortex Increased (excitatory)

* A2a receptor agonists inhibit dopamine activation of D2 receptors (Fuxe et al., 2007); since D2Rs are inhibitory this tends to increase firing of striatopallidal neurons (Strömberg et al., 2000). A2a antagonists reduce striatopallidal firing (Strömberg et al., 2000). These effects are best seen in the presence of D2 receptor stimulation (Strömberg et al., 2000; Tanganelli et al., 2004). A similar situation obtains with D3 receptors (Torvinen et al., 2005).

† The A2a antagonist DMPX decreased glucose utilization in the rat GP (Nehlig et al., 1994), homologous to human GPe.

** A2a agonists increase striatopallidal GABA release (Mayfield et al., 1993; Antonelli et al., 2006; Mingote et al., 2008), including accumbens-ventral pallidum GABA release (Mingote et al., 2008), and antagonists decrease it (Mayfield et al., 1993). ¶ Dopamine D2 agonists also increase metabolism in the STN, as determined by ex vivo [14C]2-deoxyglucose studies (Trugman, 1995). Average scaled rCBF from VOIs centered on the approximate atlas coordinates of the left and right STN (±10, −17, −3) (Mai et al., 1997) changed as follows with SYN115: 20mg, −2.5%; 60mg, −4.5%. This result could reflect a failed prediction of the model, or in this small nucleus it could merely represent imperfect anatomical localization or partial volume effect of surrounding tissue. The Supplementary Table 7, p. 2 present in vivo study does not have corresponding spatial resolution, and the STN is not easily defined on the structural images we acquired. ‡ Firing of neurons in human GPi correlates strongly with regional metabolism in thalamus (Eidelberg et al., 1997). Decreased rCBF in thalamus is the most significant effect observed in the present study. § Even if thalamocortical neurons decrease firing, predicting the cortical flow response is not straightforward for several reasons. First, in cortex, local inhibitory neurons and recurrent axons contribute a large portion of the axon termini, so that cortical CBF changes need not reflect primarily anatomically distant effects (such as thalamocortical input) (Buzsáki et al., 2007). Second, the human A2a receptor is expressed in various regions outside the striatum, most notably in the GPe but also in cortex, albeit at a ~10- fold lower density (Svenningsson et al., 1997). Thus, A2a receptors may affect cortex directly. Third, the A2a receptor has physiological roles other than its influence on D2- like dopamine receptors. For instance, A2a receptors also influence glutamatergic transmission such that A2a antagonists are expected to reduce glutamate release in cortex (Cunha et al., 2008). Since in cortex the major predictor of metabolism (hence rCBF) is glutamate release (Sibson et al., 1998), the decreased cortical rCBF we see in this study may be explained by A2a-mediated inhibition of glutamate release. An A2a antagonist challenge study did not find substantial cortical decreases in glucose metabolism in rats (Nehlig et al., 1994), but like SYN115 in this study, dopamine D2 and D3 agonists that inhibit the indirect pathway also decreased rCBF in primate cortical regions (Black et al., 2002a; Black et al., 2002b; Sánchez-Pernaute et al., 2007).

Reference List

Antonelli T, Fuxe K, Agnati L, Mazzoni E, Tanganelli S, Tomasini MC, Ferraro L (2006) Experimental studies and theoretical aspects on A2A/D2 receptor interactions in a model of Parkinson's disease. Relevance for L-dopa induced dyskinesias. J Neurol Sci 248:16-22.

Black KJ, Hershey T, Koller JM, Carl JL, Perlmutter JS (2002a) Mapping and quantification of dopamine D2 receptor activation. J Neuropsychiatr Clin Neurosci 14:118-119.

Black KJ, Hershey T, Koller JM, Videen TO, Mintun MA, Price JL, Perlmutter JS (2002b) A possible substrate for dopamine-related changes in mood and behavior: prefrontal and limbic effects of a D3-preferring dopamine agonist. Proc Natl Supplementary Table 7, p. 3

Acad Sci U S A 99:17113-17118.

Buzsáki G, Kaila K, Raichle M (2007) Inhibition and brain work. Neuron 56:771-783.

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Supplementary Table 8

Output from SPM analysis of regional increases during vs. before levodopa infusion. Clusters shown here were defined by contiguous voxels in brain with a t value corresponding to p<0.001 (uncorrected). Highlighted p values indicate points or clusters that would be considered significant at p<0.05 or p<0.10 by the statistical method given in the column heading. The pre-specified statistical analysis method was cluster false discovery rate (FDR) < 0.05 (second column, to the left of the column titled k≡). WM = white matter.

volume p(FWE-cor) p(FDR-cor) k≡ (mm³) p(unc) p(FWE-cor) p(FDR-cor) T Z≡ p(unc) x,y,z (mm) anatomy 0.000 0.000 89 2.4 0.000 0.539 0.788 5.22 4.17 0.000 28.5 -3 15 R claustrum 0.709 0.788 4.97 4.03 0.000 34.5 -21 24 R insula 0.956 0.788 4.46 3.72 0.000 28.5 -15 12 R putamen/claustrum 0.668 0.278 10 0.3 0.070 0.607 0.788 5.12 4.11 0.000 61.5 -15 27 R lateral postcentral gyrus BA 3 0.543 0.278 12 0.3 0.049 0.921 0.788 4.57 3.79 0.000 -10.5 -63 -3 L occipital cortex 1.000 0.842 3.83 3.32 0.000 -13.5 -54 -6 L occipital cortex 0.734 0.278 9 0.2 0.083 0.946 0.788 4.5 3.75 0.000 -34.5 -27 -9 L temporal lobe WM near hippocampus 0.734 0.278 9 0.2 0.083 0.967 0.788 4.41 3.69 0.000 25.5 33 9 R frontal lobe WM 0.797 0.278 8 0.2 0.101 0.980 0.788 4.33 3.64 0.000 31.5 -24 -15 R hippocampus 0.432 0.278 14 0.4 0.036 0.993 0.788 4.2 3.56 0.000 7.5 -66 12 R occipital cortex 0.797 0.278 8 0.2 0.101 0.996 0.788 4.14 3.52 0.000 19.5 -45 -6 R occipital cortex 0.734 0.278 9 0.2 0.083 0.996 0.788 4.13 3.51 0.000 -46.5 -24 24 L inferior parietal lobule (WM) 0.976 0.392 4 0.11 0.235 0.997 0.788 4.09 3.49 0.000 -16.5 48 0 L medial frontal gyrus (BA 10), WM 0.856 0.278 7 0.2 0.122 0.998 0.788 4.09 3.49 0.000 -1.5 -27 -15 midbrain near pons 0.992 0.445 3 0.08 0.303 1.000 0.842 3.91 3.37 0.000 -16.5 -45 -9 L occipital cortex 0.992 0.445 3 0.08 0.303 1.000 0.842 3.82 3.31 0.000 13.5 -81 27 R cuneus, BA 18 0.976 0.392 4 0.11 0.235 1.000 0.842 3.79 3.29 0.001 19.5 -63 27 WM in R precuneus, BA 7 0.998 0.502 2 0.05 0.402 1.000 0.842 3.77 3.28 0.001 43.5 -36 30 WM in R inferior parietal lobule, BA 40 0.976 0.392 4 0.11 0.235 1.000 0.842 3.77 3.27 0.001 52.5 -66 9 R middle temporal gyrus, BA 37 0.998 0.502 2 0.05 0.402 1.000 0.916 3.69 3.22 0.001 43.5 -30 51 R postcentral gyrus, BA 2 1.000 0.563 1 0.03 0.563 1.000 0.916 3.63 3.18 0.001 7.5 33 -12 R inferior rostral gyrus 1.000 0.563 1 0.03 0.563 1.000 0.916 3.61 3.17 0.001 34.5 -72 3 WM near R middle occipital gyrus BA 19 1.000 0.563 1 0.03 0.563 1.000 0.916 3.57 3.13 0.001 28.5 21 -12 R inferior frontal gyrus, BA 47 1.000 0.563 1 0.03 0.563 1.000 0.916 3.56 3.13 0.001 13.5 -69 0 R occipital cortex