Ventral Tegmental Area/Midbrain Functional Connectivityand Response to Antipsychotic

SUPPLEMENTARY INFORMATIONHadley, et al

Ventral Tegmental Area/Midbrain Functional Connectivityand Response to Antipsychotic Medicationin Schizophrenia

Jennifer A. Hadley, Rodolphe Nenert, Nina V. Kraguljac, Mark S. Bolding, David M. White,Frank M. Skidmore, Kristina M. Visscher, Adrienne C. Lahti

SUPPLEMENTARY TABLES

Table S1.Regions exhibiting significant ventral tegmental area (VTA)/midbrain functional connectivity in controls.

Table S2. Regions exhibiting significant VTA/midbrain functional connectivity in pre-treatment, unmedicated patients with schizophrenia.

Table S3. Regions exhibiting significant VTA/midbrain functional connectivity in post-treatment patients.

Table S4. Regions whose VTA/midbrain connectivity is significantly correlated with treatment response.

SUPPLEMENTARY FIGURES

Figure S1. BPRS total values for all time points.

Figure S2. VTA/midbrain functional connectivity patterns in participant groups.

Figure S3. MOC functional connectivity patterns in healthy controls.

Figure S4. Relationship between VTA connectivity to left thalamus and treatment response.

Figure S5. Relationships between VTA functional connectivity in unmedicated patients and residualized BPRS score at six weeks.

Figure S6.Results of reliability analysis.

Table S1.
Regions exhibiting significant VTA/midbrain functional connectivity in controls1.
Brain regions2 / Voxels in Cluster / Hem. / Voxels in Region / Peak Coordinates3 / Peak t / PFDR4
X / Y / Z
Cluster 1 / 43174 / 0 / -18 / -6 / 10.93 / < 0.001
Cortical Structures
Superior frontal gyrus / B / 1145
Middle frontal gyrus / B / 2062
Inferior frontal gyrus / B / 2141
Superior frontal gyrus / B / 1601
Supplementary motor area / B / 671
Paracentral Lobule / B / 295
Inferior frontal gyrus / B / 576
Precentral gyrus / B / 1321
Postcentral gyrus / B / 375
Rolandic operculum / B / 920
Superior temporal gyrus / L / 388
Heschl’s gyrus / L / 275
Middle temporal gyrus / B / 297
Inferior temporal gyrus / L / 42
Superior parietal gyrus / L / 347
Inferior parietal gyrus / L / 1125
Angular gyrus / L / 181
Supramarginal gyrus / L / 282
Precuneus / B / 1456
Superior occipital gyrus / L / 40
Middle occipital gyrus / L / 495
Cuneus / L / 117
Calcarine fissure / L / 698
Lingual/Fusiform gyrus / B / 1727
Subcortical & Limbic Structures
Amygdala / B / 199
Hippocampus/Parahippocampus / B / 1045
Caudate nucleus / B / 668
Putamen/Pallidum / B / 1330
Thalamus / B / 849
Insula / B / 2029
Anterior cingulate cortex / B / 540
Middle cingulate cortex / B / 2355
Posterior cingulate cortex / L / 44
Cerebellar Structures
Cerebellum / B / 1365
Vermis / B / 323
Cluster 2 / 1528 / 21 / -52 / 45 / 3.97 / 0.014
Inferior parietal gyrus / R / 187
Supramarginal gyrus / R / 521
Angular gyrus / R / 328
Precuneus / R / 82
Abbreviations: g., gyrus; Hem., hemisphere; L, left; R, right;B, bilateral.
1Regions containing fewer than 25 voxels were not included in table (unless relevant to discussion).
2Regions defined according to the AAL atlas in SPM8.
3Reported in Montreal Neurologic Institute coordinates (X, Y, and Z).
4All comparisons were FDR-corrected at the cluster-level for PFDR ≤ 0.05.
Table S2.
Regions exhibiting significant VTA/midbrain functional connectivity in pre-treatment, unmedicated patients with schizophrenia1.
Brain regions2 / Voxels in Cluster / Hem. / Voxels in Region / Peak Coordinates3 / Peak t / PFDR4
X / Y / Z
Cluster 1 / 2948 / 0 / -14 / -8 / 10.37 / 0.001
Olfactory cortex / R / 32
Caudate nucleus / B / 501
Putamen / B / 65
Thalamus / B / 220
Cerebellum / L / 74
Vermis / B / 108
Abbreviations: Hem., hemisphere; L, left; R, right; B, bilateral; VTA, ventral tegmental area.
1Regions containing fewer than 25 voxels were not included in table (unless relevant to discussion).
2Regions defined according to the AAL atlas in SPM8.
3Reported in Montreal Neurologic Institute coordinates (X, Y, and Z).
4All comparisons were FDR-corrected at the cluster-level for PFDR ≤ 0.05.
Table S3.
Regions exhibiting significant VTA/midbrain functional connectivity in post-treatment patients with schizophrenia1.
Brain regions2 / Voxels in Cluster / Hem. / Voxels in Region / Peak Coordinates3 / Peak t / PFDR4
X / Y / Z
Cluster 1 / 11133 / -2 / -18 / -6 / 12.17 / < 0.001
Superior temporal gyrus / B / 604
Heschl’s gyrus / L / 176
Middle temporal gyrus / R / 562
Supramarginal gyrus / R / 94
Precuneus / R / 174
Calcarine fissure / R / 115
Fusiform/Lingual gyrus / B / 808
Hippocampus/Parahippocampus / B / 1177
Caudate nucleus / L / 70
Putamen / L / 134
Thalamus / B / 1806
Insula / L / 260
Cerebellum / B / 727
Vermis / 235
Cluster 2 / 1398 / -42 / -6 / 2 / 5.16 / 0.013
Rolandic operculum / L / 187
Putamen / L / 341
Insula / L / 524
Cluster 3 / 1481 / 16 / -70 / 18 / 4.56 / 0.011
Superior occipital gyrus / R / 58
Cuneus / R / 444
Calcarine fissure / R / 666
Cluster 4 / 2768 / -20 / -10 / 50 / 3.93 / < 0.001
Superior frontal gyrus / L / 1105
Middle frontal gyrus / L / 697
Supplementary motor area / L / 103
Precentral gyrus / L / 100
Cluster 5 / 2391 / 22 / 3 / 38 / 3.87 / 0.001
Superior frontal gyrus / R / 42
Middle frontal gyrus / R / 105
Inferior frontal gyrus / R / 157
Supplementary motor area / R / 405
Precentral gyrus / R / 193
Cluster 6 / 1115 / -21 / -78 / 15 / 3.75 / 0.033
Cuneus / L / 236
Lingual gyrus / L / 276
Cluster 7 / 2142 / 34 / -9 / -9 / 3.66 / 0.001
Inferior frontal gyrus / R / 98
Rolandic operculum / R / 177
Superior temporal gyrus / R / 209
Putamen / R / 258
Insula / R / 614
Abbreviations: g., gyrus; Hem., hemisphere; L, left; R, right; B, bilateral; VTA, ventral tegmental area.
1Regions containing fewer than 25 voxels were not included in table (unless relevant to discussion).
2Regions defined according to the AAL atlas in SPM8.
3Reported in Montreal Neurologic Institute coordinates (X, Y, and Z).
4All comparisons were FDR-corrected at the cluster-level for PFDR ≤ 0.05.
Table S4.
Regions whose VTA/midbrain connectivity is significantly correlated with treatment response1.
Brain regions2 / Voxels in Cluster / Hem. / Voxels in Region / Peak Coordinates3 / Peak t / PFDR4
X / Y / Z
Positively Correlated with Treatment Response
Cluster 1 / 2001 / -15 / 0 / 45 / 6.32 / 0.010
Middle frontal gyrus / L / 38
Supplementary motor area / B / 551
Paracentral lobule / B / 359
Precentral gyrus / R / 83
Anterior cingulate cortex / L / 53
Middle cingulate cortex / L / 170
Negatively Correlated with Treatment Response
Cluster 1 / 5065 / -6 / 48 / 22 / 6.15 / < 0.001
Superior frontal gyrus / B / 621
Middle frontal gyrus / L / 634
Inferior frontal gyrus / B / 857
Superior frontal gyrus / B / 2154
Middle frontal gyrus / L / 123
Anterior cingulate cortex / B / 375
Cluster 2 / 5414 / 6 / -52 / 34 / 5.96 / < 0.001
Inferior parietal gyrus / R / 114
Angular gyrus / R / 373
Supramarginal gyrus / R / 239
Precuneus / B / 1463
Superior occipital gyrus / R / 112
Cuneus / B / 507
Calcarine fissure / B / 234
Lingual gyrus / B / 78
Middle cingulate cortex / B / 528
Posterior cingulate cortex / B / 438
Thalamus / L / 96
Cluster 3 / 1795 / -42 / -70 / 28 / 4.96 / 0.005
Middle temporal gyrus / L / 349
Inferior parietal gyrus / L / 224
Angular gyrus / L / 775
Middle occipital gyrus / L / 235
Cluster 4 / 3850 / -26 / -66 / -26 / 4.73 / < 0.001
Calcarine fissure / B / 94
Fusiform/Lingual gyrus / B / 958
Hippocampus/Parahippocampus / L / 246
Cerebellum / B / 1963
Vermis / 848
Abbreviations: HC, healthy controls; Hem., hemisphere; L, left; R, right; SZ0, unmedicated patients with schizophrenia; SZ1, post-treatment patients with schizophrenia.
1Regions containing fewer than 25 voxels were not included in table (unless relevant to discussion).
2Regions defined according to the AAL atlas in SPM8.
3Reported in Montreal Neurologic Institute coordinates (X, Y, and Z).
4All comparisons were FDR-corrected at the cluster-level for PFDR ≤ 0.05.
Figure S1. BPRS Total Values for All Time Points. Solid black lines indicate values for patients who completed all time points of the study (n = 16). Dashed black lines indicate values for patients who completed all but the last time point of the study (n = 2), whose final value was carried forward to calculate treatment response. Dashed red lines indicate values for patients who did not complete the study (n = 3).
Figure S2. VTA/midbrain functional connectivity patterns in participant groups.(A) Regions exhibiting VTA/midbrain functional connectivity in controls (n= 21). (B) Regions exhibiting VTA/midbrain functional connectivity in unmedicated patients with schizophrenia (n= 21). (C) Regions exhibiting VTA/midbrain functional connectivity in patients with schizophrenia after one week of treatment (n= 21). Allstatistical maps were FDR-corrected at the cluster-level for PFDR < 0.05 (line indicates Z-score threshold). Results are overlaid on a single-subject high resolution T1 image of an extracted brain displayed in neurologic convention (left on left side)
Figure S3. Middle occipital cortex (MOC) functional connectivity pattern in healthy controls (n = 21).All statistical maps were FDR-corrected at the cluster-level for PFDR < 0.05 (line indicates Z-score threshold). Results are overlaid on a single-subject high resolution T1 image of an extracted brain displayed in neurologic convention (left on left side).
Figure S4. VTA Connectivity to the Left Thalamus is Not Related to Treatment Response. (A) Relationship between VTA connectivity to left thalamus (6-mm sphere centered at MNI coordinates -8, -17, 5) and treatment response in (A) unmedicated patients with schizophrenia (n= 18) and (B) patients after one week of antipsychotic treatment (n= 18).
Figure S5. Relationships between VTA Functional Connectivity in Unmedicated Patients and Residualized BPRS Score at Six Weeks. Treatment response can also be calculated as the residual after the week six BPRS score is corrected for the baseline BPRS score. This alters the distribution of values such that a small value indicates better response to treatment, and a large value indicates worse response to treatment. (A) Regions where pre-treatment VTA functional connectivity is negatively correlated with residualized treatment response (n= 18). (B) Regions where pre-treatment VTA functional connectivity is positively correlated with residualized treatment response (n= 18). Note the similarity of (A) to Fig. 2B and (B) to Fig. 2A. Statistical maps were FDR-corrected at the cluster-level for PFDR < 0.05 (black line indicates Z-score threshold). Results are overlaid on a single-subject high resolution T1 image of an extracted brain displayed in neurologic convention (left on left side).
Figure S6. Results of reliability analysis.(A) Extent of repeated analyses (n= 18) showing significant positive correlation between VTA/midbrain functional connectivity and treatment response. (B) Extent of repeated analyses (n= 18) showing significant negative correlation between VTA/midbrain functional connectivity and treatment response. For both panels, each analysis was significant at PFDR< 0.05 and corrected with the false discovery rate. Results are overlaid on a single-subject high resolution T1 image of an extracted brain in neurologic convention (left on left).

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