SUPPLEMENTARY INFORMATION
Methods: Region of Interest (ROI) Definition
The ROI for extracting the metabolic data were defined on the MNI template composed
of MRI images from multiple individuals’ brains that is provided within the SPM software.
The ROI in the orbitofrontal cortex (OFC) was defined on coronal slices to encompass
the medial and lateral orbital gyri running between the beginning and end of the olfactory
sulcus (Fig. S1 (d)). The ventrolateral prefrontal cortex (vlPFC) ROI encompassed the
inferior frontal gyrus from 6 slices (12 mm) ventral to the bi-commissural plane extending
dorsally a total of 6 slices (2 mm) ventral to the bi-commissural plane (Fig. S1 (b)). The
anteromedial prefrontal cortex (amPFC) ROI encompassed the superior frontal gyrus
situated anterior to the anterior cingulate gyrus (or gyri) from 8 slices (20 mm) ventral to
the bi-commissural plane extending dorsally a total of 8 slices (34 mm) dorsal to the bicommissural plane. This region corresponded to BA 9 (Fig. S1 (f)). The perigenual
anterior cingulate (pgACC) ROI encompassed the anterior cingulate gyrus (or gyri in
cases where the cingulate gyrus was bifurcate) from 3 slices ventral to the ventral aspect
of the corpus callosum (subgenual), extending dorsally 13 slices through the ACC
anterior to the genu of the corpus callosum (pregenual) (Figs. S1 (a, f)). The dorsolateral
prefrontal cortex (DLPFC) was placed on horizontal sections as a series of circular ROIs
of 2 cm radius situated over the middle frontal gyrus, beginning in the plane located
immediately dorsal to the dorsum of the corpus callosum and extending dorsally a total
of 6 slices (i.e., from z=32 mm to z=42 mm; Fig. S1 (c)). Note that within each subject’s
image data the masking procedure described below excludes from analysis any voxel
that is not composed of grey matter, so that the portion of the ROI located outside the
brain edge (see Fig. S1 (c)) does not contribute to the regional metabolic measurement.
The amygdala ROI was defined as described in (Drevets et al 2002) (Fig. S1 (e)). The
ventral striatum ROI was placed as an oval (10 x 8 mm) centered in ventral striatum gray
matter of the accumbens area situated anterior to the anterior commissure immediately
ventral to the ventral tip of the internal capsule and then extending dorsally two additional
slices (Fig. S1 (b)). The insula (AI) ROI encompassed the insular cortex traced in
sequential sagittal planes from 38 mm to 48 mm, bilaterally (measurements obtained
from this ROI also would have been influenced by radioactivity in the adjacent superior
temporal gyrus and inferior frontal gyrus) (Fig. S1 (d)).
Each subjects’s MRI then was spatially transformed to the template image and each ROI
was manually repositioned as needed according to each individual’s anatomical
landmarks, using the published illustrations from Mai et al (2003) and Talairach and
Tournoux 1988). The ROI were converted to binary masks and then transformed into the
native space of the subject’s MRI. Binary gray matter masks were then applied to these
regions to include only gray matter pixels in the analysis. The ROI were then transferred
to the coregistered PET images, and the mean regional metabolic activity was obtained.
A measure of mean activity across the entire brain, calculated as the mean of all gray
matter pixels in the PET image, was used to normalize the regional measures and factor
out nonspecific global effects. For each region, a difference measurement was obtained
by subtracting the pre-treatment from the post-treatment values.
SUPPLEMENTARY RESULTS
Table S1.Quantitative whole-brain cerebral glucose metabolism (CMRglu) for individual subjects in
pramipexole and placebo groups. As described in the manuscript, the quantitative data could not be
obtained in 8 of the 30 images due to technical problems with generating the cardiac input function
(because all of the serial blood draws could not be obtained from the intravenous cannulae, which
was prone to occlusion during repeated blood sampling).
PLACEBO
PRAMIPEXOLE
Baseline
CMRglu
Subject
md/min/dl
1
.0619
2
.0738
3
.
4
.0617
5
.0966
6
.0524
7
.
8
.0564
Post-treatment
CMRglu
mg/min/dl
.0566
.0606
.0703
.
.0773
.0641
.0573
.0691
1
2
3
4
5
6
7
.
.0504
.
.0666
.0613
.0632
.0535
.0588
.0485
.
.0558
.1244
.
.
Mah et al.
Neural Effects of Pramipexole
Table S2. Changes in normalized regional glucose metabolism in response to pramipexole or placebo identified by voxel-wise
analysis.a The region implicated by each coordinate set is identified and, for cortical areas, the corresponding Brodmann area is
approximated using stereotaxic atlases of Talairach et al. (1988) and Mai et al. (2004).
BASELINE > PRAMIPEXOLE
REGIONb
Medial Frontopolar Cortex (BA 10p)
Number
y,
zc
Z-valued
of
level
of voxels
voxels in
corrected in cluster
corrected
cluster
p-value
p-value
5
5.51e,f
65,
5,
62, 13
3.88e
3,
49,
0
3.24e
.001
L. Inferior Parietal Lobule (BA 40)
1309
-61, -36, 40
4.17e
<.001
Precuneus (BA7)
145
-1,
-66, 38
3.76
.99
Mid-Cingulate Cortex (BA 23/24)
403
0,
-16, 22
3.58
.20
-3,
-29, 19
3.52
L. Ventrolateral PFC (BA 10p, 45)
L. Inferotemporal Gyrus (BA 20/21)
692
358
4,
-6,
23
3.28
-28,
51,
9
3.40e
-35,
40, 15
3.18e
-37,
43,
3.04e
3
-41, -32, -19
3.18
-47, -46, -16
3.02
.017
.30
y,
Z-valued
Number
-4,
x,
zc
Cluster-
1079
x,
BASELINE > PLACEBO
Clusterlevel
Mah et al.
Neural Effects of Pramipexole
PRAMIPEXOLE > BASELINE
R. Posterior Cingulate Cortex (BA
1547
12,
-45,
9
4.79e
<.001
PLACEBO > BASELINE
590
29, 30)
R. Posterior Hippocampus
L. Premotor Cortex (BA6)
1547
1521
36,
-9,
-38,
-19,
0
4.30e
<.001
e
<.001
44 4.72
-18, -15,
47 4.08e
1521
-24, -19,
53 3.48e
<.001
R. Post Central Gyrus (BA 1,3,7)
214
40, -23,
46 4.69
.83
R. Ventrolateral PFC (BA 46)
304
27,
34,
16 4.37
.47
L. Accumbens Area
235
-12,
8,
-6 3.82
.75
Hypothalamus
235
-2,
0,
-2 3.19
.75
R. Superior Temporal Gyrus (BA
315
53, -17,
6
3.71
.43
22)
321
32, -58,
23 3.32
.41
L. Primary Motor Cortex (Precentral
8,
-58, 14
3.16
28, -62, 16
3.11
.11
G) (BA 4)
376
31, -38, 54 3.66
.44
R. Superior Parietal Lobule (BA 7)
376
24, -49, 37 3.20
.44
Lingual Gyrus (BA 18)
590
24, -55,
1 3.34
.11
L. Superior Temporal Gyrus (BA 22)
411
-33, -58, 23 2.99
.36
L. Middle Occipital Gyrus (BA 19)
411
-38, -75, 24 2.99
.36
Mah et al.
Neural Effects of Pramipexole
a. Areas where mean activity increased or decreased during pramipexole treatment relative to the pretreatment baseline condition
are indicated by the “Pramipexole>Baseline” and “Baseline>Pramipexole” conditions, respectively. Similarly, areas where mean
activity increased or decreased during placebo administration are indicated by the “Placebo>Baseline” and “Baseline>Placebo”
conditions, respectively.
b. Stereotaxic coordinates locate peak voxel t-values corresponding to p<0.001 that also are part of clusters of significant voxels that
are significant at p<.05 by the cluster test (Poline et al 1997).
c. Coordinates denote the distance in mm from the anterior commissure, with positive x and y indicating right and anterior,
respectively, and positive z dorsal to a plane containing both the anterior and posterior commissures.
d. The voxel level Z-value for the voxel containing the peak difference between conditions.
e. Significant at p<0.05 after correction for multiple comparisons using the cluster test (Poline et al 1997).
f. Significant at the voxel-level p<0.05 after correction for multiple comparisons using the False Discovery Rate test.
Abbreviations: L- left; R- right; PFC- prefrontal cortex; 10p- BA 10 polar (Ongur et al. 2003).
Mah et al.
Neural Effects of Pramipexole
SUPPLEMENTARY FIGURE LEGENDS
Figure S1.
Surface renderings of regions-of-interest (ROIs) on axial, coronal, and sagittal views of
brain.
Axial sections showing (a) perigenual anterior cingulate cortex (pgACC); crosshair
placed on left pgACC; (b) ventral striatum (VS) and ventrolateral prefrontal cortex
(VLPFC); crosshair placed on right VS; (c) dorsolateral prefrontal cortex (DLPFC).
Coronal sections showing (d) orbital frontal cortex (OFC) and anterior insula (AI);
crosshair placed on right AI, and (e) amygdala; crosshair placed on right.
Sagittal section showing (f) anteromedial prefrontal cortex (amPFC) and pgACC;
crosshair placed on left pgACC.
Figure S2.
Scatterplot of association between improvement in depressive symptomatology on MontgomeryAsberg Depression Rating Scale (MADRS; Montgomery and Asberg (1979) and baseline metabolism
in left orbitofrontal cortex (Spearman’s rho = -.87, p=.01).
Mah et al.
Neural Effects of Pramipexole
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