Reduced Inferior Frontal Gyrus Activation During Response

Roberts et al.
Reduced Inferior Frontal Gyrus Activation During Response Inhibition to
Emotional Stimuli in Youth at High Risk of Bipolar Disorder
Supplemental Information
Description of Facial Stimuli
All the gray-scaled elected images were from the open mouth collection. The
identities of the faces used were numbers: 1, 3, 6, 7, 8, 10, 23, 25, 27, 32, 35, and 36. All
images were normalized for size and luminance. All models were Caucasian given that
approximately 86% of the Australian population report Caucasian ancestry (Australian 2006
Census). We used calm faces as a proxy for neutral in line with Hare et al.’s (1) previous
study in adolescent and adult subjects.
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Roberts et al.
Table S1. Go/No-Go behavioral results for individual conditions. Results are expressed as
mean (SD).
Bipolar ‘at-risk’
(n = 47), mean (SD)
Successful Target %
Fear
Happy
Calm (in fear context)
Calm (in happy context)
Total Calm
Male
Female
Total all conditions
Successful Non-target %
Calm (in fear context)
Calm (in happy context)
Fear
Happy
Total Calm
Female
Male
Total all conditions
Controls (n = 49),
mean (SD)
t
98 (4.1)
99 (2.2)
95 (6.5)
95 (10.1)
95 (7.3)
98 (8.1)
100 (1.3)
97 (3.6)
94 (11.3)
99 (2.7)
93 (12.6)
93 (11.0)
93 (11.3)
98 (5.5)
99 (4.2)
96 (5.6)
2.12*
0.72
1.30
0.79
1.12
-0.07
1.86
1.65
95 (7.8)
92 (7.5)
96 (7.1)
82 (20.1)
93 (5.0)
90 (6.6)
93 (8.5)
92 (5.7)
94 (12.3)
89 (10.7)
91 (12.9)
83 (19.7)
91 (8.4)
89 (10.7)
92 (8.9)
91 (9.1)
0.06
1.45
2.39*
-0.26
0.92
0.23
0.60
0.62
Successful Target: Reaction Time
Fear
754 (179.4)
772 (124.7)
Happy
684 (89.0)
702 (88.7)
Calm (in fear context)
774 (125.7)
803 (128.0)
Calm (in happy context)
821 (145.6)
824 (135.5)
Total Calm
799 (130.8)
835 (128.2)
Male
697 (120.3)
708 (91.2)
Female
686 (128.1)
683 (88.5)
Total all conditions
738 (112.7)
748 (82.3)
* independent t-tests: p < 0.05 for the bipolar ‘at-risk’ group versus controls.
-0.57
-0.99
-1.10
-0.11
-1.17
-0.55
0.12
-0.45
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Roberts et al.
Effects of Current Depression, Gender, and Proband Type
We subsequently repeated the contrast for the inhibition of responses to Fear (Fear
Distractors minus Fear Targets) after removing the two participants from the control group
who were depressed at the time of scanning. When we excluded the two controls with current
depression, the groups still did not differ significantly on age, years of education, or in gender
ratio. The effect remained significant, exceeding a conservative threshold at both the peak
voxel level (p = 0.005, family-wise error (FWE) corrected; t = 5.41; z = 5.03; Montreal
Neurological Institute (MNI) coordinates: x = -21, y = 11; z = -17) and at the cluster-level (p
= 0.024 FWE corrected; cluster size = 34 voxels). In addition, we performed a series of twosample t-tests for this contrast in at-risk for bipolar disorder (AR-BD) participants only, to
assess effects of gender, as well as proband status (i.e., affected parent versus affected
sibling), and proband illness type (i.e., bipolar I versus bipolar II disorder). For all three ttests there were no significant effects within a whole brain analysis, or left inferior frontal
gyrus (IFG) region of interest analysis (defined as a sphere of 10 mm radius from -21, 11,
-17).
Specificity of the IFG Result to Response Inhibition of Fear
To formally test the specificity of our finding for the inhibition of fear (versus
inhibition of calm or happy) faces, we next employed a full factorial, mixed design analysis
of variance including two levels of the between-subject factor of group (AR-BD/control),
three levels of the within-subject factor of emotional valence (fear/happy/calm), and two
levels of the within-subject factor of task (Go/No-Go). This model enables a range of
direction and non-directional contrasts but based on the results of the above random-effects
analysis we only report below the contrasts relevant to verifying the specificity of reduced
IFG activity for the inhibition of Fear stimuli. Contrasts for these individual effects were
entered into the second level SPM analyses. F statistics are reported for undirected group
contrasts and t statistics are reported for directional post-hoc tests of any significant effects.
All relevant contrasts showed strong and robust effects in the left IFG. For example, the
inhibition of responses to Fear relative to the inhibition of responses to Happy faces (Fear
Distractors minus Fear Targets > Happy Distractors minus Happy Targets) revealed a highly
significant group effect in the left IFG cluster (peak voxel level p = 0.011, FWE corrected; F
= 26.0; z = 4.89; Brodmann area (BA) 47; MNI peak coordinates: x = -21, y = 11; z = -20).
Subsequent post-hoc directional t-tests showed this difference reflected increased brain signal
in the left IFG in the control group over the AR-BD group (peak voxel level p = 0.005, FWE
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Roberts et al.
corrected; t = 5.1; z = 5.83; BA 47; MNI peak coordinates: x = -21, y = 11; z = -20). No
voxels approached significance in the opposite direction (AR-BD > controls). Similarly the
inhibition of responses to Fear faces relative to responses to Calm faces (Fear Distractors
minus Fear Targets > Calm Distractors minus Calm Targets) showed a robust effect in the
left IFG cluster (p < 0.001, FWE corrected; F = 43.5; z = 6.34; BA 47; MNI peak
coordinates: x =
-21, y = 11; z = -17). Post hoc t-tests showed that this was also driven by
the contrast of healthy controls over the AR-BD cohort (p < 0.001, FWE corrected; t = 6.6; z
= 6.45; BA 47; MNI peak coordinates: x = -21, y = 11; z = -17). Of note, these effects further
exceeded threshold when repeating the analysis without the two participants from the control
group who were depressed at the time of scanning (peak voxel level p = 0.003, FWE
corrected; F = 29.1; z = 5.18; BA 47; MNI peak coordinates: x = -21, y = 8; z = -20 for the
interaction between Fear and Happy; peak voxel level p < 0.001, FWE corrected; F = 48.2; z
= 6.67; BA 47; MNI peak coordinates: x = -21, y = 11; z = -17 for the interaction between
Fear and Calm).
Subsequent reanalyses using the full factorial model but excluding those currently
prescribed psychotropics (n = 8 AR-BD and n = 2 healthy control) showed significant effects
which exceeded peak-voxel threshold (peak voxel level p = 0.009, FWE corrected; F = 26.69;
z = 4.95; BA 47; MNI peak coordinates: x = -21, y = 11; z = -20 for the interaction between
Fear and Happy; peak voxel level p < 0.001, FWE corrected; F = 46.34; z = 6.53; BA 47;
MNI peak coordinates: x = -21, y = 11; z = -17 for the interaction between Fear and Calm).
1. Hare TA, Tottenham N, Galvan A, Voss HU, Glover GH, Casey BJ (2008): Biological
substrates of emotional reactivity and regulation in adolescence during an emotional Go/NoGo task. Biol Psychiatry 63: 927-934.
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