Supplementary Information
Overlapping expression of serotonin transporters and neurokinin-1 receptors in
posttraumatic stress disorder: a multi-tracer PET study
Andreas Frick, Fredrik Åhs, Åsa Michelgård Palmquist, Anna Pissiota, Ulrika Wallenquist,
Manuel Fernandez, My Jonasson, Lieuwe Appel, Örjan Frans, Mark Lubberink, Tomas
Furmark, Lars von Knorring, Mats Fredrikson
Additional analyses
Correlation analyses
When substituting the original Pearson’s correlations with Spearman’s rank-order
correlations, the difference in correlations between patients and controls remained
(Supplementary Table 2).
Regression analyses
In addition to the ordinary least squares regressions used in our original analyses, we
conducted both robust and rank-based multiple regressions for the amygdala, safeguarding
against the effects of potential outliers and/or extreme values as well as non-normally
distributed data using two different techniques. These analyses yielded results almost identical
to those obtained originally because all p-values remained significant (Supplementary Table
3), including a significant interaction term.
Supplementary Table 1. Participant demographic and clinical characteristics.
PTSD patients Control group
Statistic
P
Age mean (SD)
38.7 (13.0)
34.0 (9.7)
t=1.156 .257
Sex, men, women
8M, 8W
8M, 8W
χ2=0
1
2
Handedness
16 right, 0 left 16 right, 0 left
χ =0
1
Symptom duration years mean (SD) 11.5 (8.8)
Trauma type
Combat
8
Traffic accident
3
Witness suicide
2
Sexual assault
2
Domestic violence
1
CAPS
Total score
68.3 (16.7)
Arousal
19.9 (5.9)
Avoidance
26.5 (5.4)
Intrusion
22.0 (8.0)
MADRS Total score
20.9 (7.1)
Comorbidity
Depression
12
GAD
3
OCD
3
PD
4
CAPS: Clinician-Administered PTSD Scale, GAD: General Anxiety Disorder, MADRS:
Montgomery-Åsberg Depression Rating Scale, OCD: Obsessive-Compulsive Disorder, PD:
Panic Disorder, PTSD: Posttraumatic stress disorder
Supplementary Table 2. Overlapping expression of serotonin transporters (SERT;
[11C]DASB binding potential, BPND) and neurokinin-1 receptors (NK1R; [11C]GR205171
influx rate, Ki) in posttraumatic stress disorder (PTSD) as compared to healthy controls (HC)
using Pearson’s and Spearman’s correlations.
Pearson’s
Spearman’s
MNI x, y, z
p
p
diff ra
diff rb
HC>PTSD
Putamen
26
8 -10
1.25
<.001
1.12
.002
Thalamus
-14 -20 6
1.16
.001
1.12
.003
Insula
-38 -20 -2
1.09
.004
0.94
.016
Orbitofrontal gyrus
34 56 -2
0.99
.005
0.95
.011
Insula
-26 16c -14
0.83
.020
0.67
.041
PTSD>HC
Inferior temporal gyrus 46 -52 -22
-1.28
<.001
-1.04
.007
Cuneus
-6 -84 30
-1.28
<.001
-1.20
<.001
Middle cingulate cortex 10
8
34
-1.11
<.001
-1.07
.002
Orbitofrontal gyrus
6
56 -10
-1.04
.001
-.072
.026
MNI: Montreal Neurological Institute
a
Differences in Pearson’s r correlation coefficient between groups: rHC - rPTSD, as an index of
difference in overlapping expression.
b
Differences in Spearman’s r correlation coefficient between groups: rHC - rPTSD, as an index
of difference in overlapping expression.
c
The coordinate for the Spearman correlations was in -26, 16, -14.
Supplementary Table 3. Multiple ordinary least square regressions, robust regressions, and
rank-based regressions regressing CAPS total score on amygdala neurochemical parameters,
including age and sex as covariates.
SERT
NK1R
SERT×NK1R
β
p
β
p
β
p
-0.31
.195
-0.08
.656
Ordinary least square regression
-0.49
.013
-0.32
.227
-0.08
.671
Robust regression
-0.48
.020
-0.36
.211
-0.10
.643
Rank-based regression
-0.45
.037
SERT: Serotonin transporter, NK1R: Neurokinin-1 receptor
Supplementary Table 4. Relationship between arousal symptom severity (Clinician-Administered PTSD Scale; CAPS Arousal score) and the
overlapping expression between neurotransmitter systems, serotonin transporter (SERT) availability ( [11C]DASB binding potential, BPND) and
neurokinin-1 receptor (NK1R) availability ( [11C]GR205171 influx rate, Ki), in posttraumatic stress disorder (PTSD).
BA
Hemisphere
MNI x, y, z
βa
Negative relationship with CAPS Arousal score
Insula
47
Left
-26
16
-10 1.689
PAG
Left
-6
-32
-2
1.212
Parahippocampal gyrus
28
Right
18
-8
-26 1.167
Precuneus
31
Right
6
-52
22
1.016
Calcarine
17
Left
-2
-84
6
0.969
Cuneus
7
Left
-14
-80
34
0.962
Superior frontal gyrus
10
Right
26
48
22
0.955
Precuneus
31
Right
18
-64
22
0.947
Supramarginal gyrus
40
Right
62
-40
34
0.935
Inferior temporal gyrus
37
Right
50
-64
-6
0.890
Middle temporal gyrus
21
Right
54
-4
-22 0.836
Cuneus
31
Left
-10
-64
22
0.816
Ventromedial prefrontal cortex
25
Left
-2
20
-10 0.806
Superior frontal gyrus
10
Left
-14
60
10
0.781
Fusiform gyrus
19
Left
-26
-52
-14 0.767
BA: Brodmann area, CAPS: Clinician-administered PTSD scale, MNI: Montreal Neurological Institute
a
Regression coefficient; b Cluster volume in mm3
p-value
Cluster volumeb
.001
<.001
.006
<.001
.003
.003
.016
.004
.001
<.001
.047
.001
.002
.006
.029
9216
2304
12544
4800
1728
832
768
1216
3968
1024
960
960
768
896
640
Supplementary Table 5. Relationship between avoidance symptom severity (Clinician-Administered PTSD Scale; CAPS Avoidance score) and
the overlapping expression between neurotransmitter systems, serotonin transporter (SERT) availability ( [11C]DASB binding potential, BPND)
and neurokinin-1 receptor (NK1R) availability ( [11C]GR205171 influx rate, Ki), in posttraumatic stress disorder (PTSD).
BA
Hemisphere
MNI x, y, z
βa
Negative relationship with CAPS Avoidance score
Inferior temporal gyrus
21
Left
-38
4
-38 1.540
Inferior temporal gyrus
20
Right
42
-8
-34 1.429
Lingual gyrus
30
Right
14
-56
6
1.347
Inferior frontal gyrus
45
Right
50
20
18
1.245
Precentral gyrus
6
Right
38
-8
54
1.191
Middle frontal gyrus
8
Left
-26
24
42
1.157
Parahippocampal gyrus
35
Right
22
-12
-30 1.096
Anterior cingulate cortex
10
Right
10
48
10
1.087
Caudate
Right
14
24
-2
1.085
Middle frontal gyrus
9
Right
42
20
34
1.055
Inferior occipital gyrus
37
Left
-50
-64
-18 1.013
Middle temporal gyrus
22
Right
62
-36
6
0.973
Brainstem
Right
2
-28
-50 0.900
Middle temporal gyrus
21
Left
-62
-44
-14 0.883
Superior frontal gyrus
10
Right
18
60
-2
0.843
Hippocampus
Left
-18
-32
-2
0.832
Posterior cingulate cortex
31
Right
6
-44
30
0.824
Supramarginal gyrus
40
Left
-54
-28
22
0.793
Inferior frontal gyrus
11
Left
-38
36
-10 0.788
Calcarine gyrus
30
Left
-14
-56
6
0.751
BA: Brodmann area, CAPS: Clinician-administered PTSD scale, MNI: Montreal Neurological Institute
a
Regression coefficient; b Cluster volume in mm3
p-value
Cluster volumeb
.009
.001
<.001
.023
.008
.011
.005
.004
.001
.019
.030
<.001
.008
<.001
.038
.025
.003
.025
.002
.010
2752
2176
1216
1280
1600
768
1344
4416
896
704
832
1600
640
1024
768
960
1728
704
704
896
Supplementary Table 6. Relationship between intrusion symptom severity (Clinician-Administered PTSD Scale; CAPS Intrusion score) and the
overlapping expression between neurotransmitter systems, serotonin transporter (SERT) availability ( [11C]DASB binding potential, BPND) and
neurokinin-1 receptor (NK1R) availability ( [11C]GR205171 influx rate, Ki), in posttraumatic stress disorder (PTSD).
Negative relationship with CAPS Intrusion score
Inferior temporal gyrus
Inferior frontal gyrus
Anterior cingulate cortex
Hippocampus
Lingual gyrus
Inferior occipital cortex
Precentral gyrus
Middle frontal gyrus
Supramarginal gyrus
Fusiform gyrus
Orbitofrontal gyrus
Precuneus
Rolandic operculum
Anterior cingulate cortex
Supramarginal gyrus
Inferior frontal gyrus
BA
Hemisphere
20
46
32
19
37
6
9
40
38
47
31
13
32
40
47
Right
Right
Left
Left
Right
Left
Right
Right
Right
Right
Right
Right
Right
Right
Left
Right
MNI x, y, z
46
46
-6
-26
22
-50
38
34
62
30
26
2
42
10
-54
46
0
24
40
-12
-56
-64
-8
40
-36
4
8
-64
-4
44
-28
40
-38
22
22
-18
-6
-18
54
30
34
-42
-18
30
10
6
22
-6
βa
p-value
Cluster volumeb
0.727
0.701
0.697
0.693
0.676
0.669
0.647
0.605
0.573
0.548
0.546
0.520
0.507
0.481
0.455
0.454
.009
.042
.018
<.001
.005
.004
.008
.037
.043
<.001
.012
.041
<.001
.005
.030
.009
1984
896
704
3904
1408
3072
704
704
1536
1024
2816
1728
640
640
1024
1024
.003
.015
.018
.042
.001
.013
.011
640
832
640
960
1600
1408
704
Positive relationship with CAPS Intrusion score
Fusiform gyrus
35
Left
-30
-28
-22 0.648
Midbrain
Right
18
-16
-10 0.613
Middle temporal gyrus
22
Left
-54
-52
14
0.607
Fusiform gyrus
37
Right
30
-36
-14 0.579
Raphe region
Right
6
-40
-26 0.570
Insula
13
Left
-30
16
-6
0.501
Lingual gyrus
18
Right
14
-84
-10 0.401
BA: Brodmann area, CAPS: Clinician-administered PTSD scale, MNI: Montreal Neurological Institute
a
Regression coefficient; b Cluster volume in mm3
Supplementary Figure 1. Box-and-whisker plot of [11C]DASB binding potential (BPND), an
index of serotonin transporter availability, in the amygdala in healthy controls (red) and
patients with posttraumatic stress disorder (PTSD; blue). No statistical difference in
[11C]DASB BPND was detected between the groups (t(29)=0.825, p=.416).
11
[ C]DASB Binding potential
0.7
0.6
0.5
0.4
Controls
PTSD
Supplementary Figure 2. Altered correlation between serotonin transporter ([11C]DASB
Binding potential) and NK1 receptor ([11C]GR205171 Ki) availability in the (A) putamen and
(B) inferior temporal gyrus (ITG) of patients with PTSD relative to healthy controls.
Supplementary Figure 3. Scatterplot and linear regression line depicting the simple
relationship between serotonin transporter (SERT) availability ([11C]DASB binding potential)
and posttraumatic stress disorder (PTSD) symptom severity, indexed by the ClinicianAdministered PTSD Scale (CAPS).
90
80
CAPS
70
60
50
40
30
-0.1
0.0
11
0.1
Amygdala [ C]DASB Binding potential
0.2
Supplementary Figure 4. Scatterplot and linear regression line depicting the simple
relationship between neurokinin-1 receptor availability ([11C]GR205171 Ki) and
posttraumatic stress disorder (PTSD) symptom severity, indexed by the ClinicianAdministered PTSD Scale (CAPS).
90
80
CAPS
70
60
50
40
30
-0.002
-0.001
0.000
11
0.001
Amygdala [ C]GR205171 Ki
0.002
Supplementary Figure 5. Neurotransmitter system associations and posttraumatic stress
disorder (PTSD) arousal symptom severity, indexed by the Clinician-administered PTSD
Scale (CAPS) Arousal Subscale. Top panel shows beta weights for relationship between
arousal CAPS score for separate simple regression models including (A) serotonin transporter
(SERT) availability ([11C]DASB BPND) and (B) neurokinin-1 receptor (NK1R) availability
([11C]GR205171 Ki) respectively, and (C) for the interaction between SERT and NK1R
availability in a multiple regression model including both SERT and NK1R availability and
the interaction. Beta coefficient images overlaid on a standard MRI image. All rows depict
slices at MNI coordinate (5, 3, -8). The colorbar indicates regression coefficients (β).
Supplementary Figure 6. Neurotransmitter system associations and posttraumatic stress
disorder (PTSD) avoidance symptom severity, indexed by the Clinician-administered PTSD
Scale (CAPS) Avoidance Subscale. Top panel shows beta weights for relationship between
arousal CAPS score for separate simple regression models including (A) serotonin transporter
(SERT) availability ([11C]DASB BPND) and (B) neurokinin-1 receptor (NK1R) availability
([11C]GR205171 Ki) respectively, and (C) for the interaction between SERT and NK1R
availability in a multiple regression model including both SERT and NK1R availability and
the interaction. Beta coefficient images overlaid on a standard MRI image. All rows depict
slices at MNI coordinate (5, 3, -8). The colorbar indicates regression coefficients (β).
Supplementary Figure 7. Neurotransmitter system associations and posttraumatic stress
disorder (PTSD) intrusion symptom severity, indexed by the Clinician-administered PTSD
Scale (CAPS) Intrusion Subscale. Top panel shows beta weights for relationship between
arousal CAPS score for separate simple regression models including (A) serotonin transporter
(SERT) availability ([11C]DASB BPND) and (B) neurokinin-1 receptor (NK1R) availability
([11C]GR205171 Ki) respectively, and (C) for the interaction between SERT and NK1R
availability in a multiple regression model including both SERT and NK1R availability and
the interaction. Beta coefficient images overlaid on a standard MRI image. All rows depict
slices at MNI coordinate (5, 3, -8). The colorbar indicates regression coefficients (β).