Supplementary Information 4: Whole-brain analyses
Supplementary Methods and Materials
Whole-brain investigation of task-related activation
To investigate regional activation associated with inhibitory function one sample T-tests were conducted on the first-level contrast images for successful (n=1133) and failed (n=1133) inhibition independently. These contrast images were calculated as described in Methods. Significance was ascribed according to a cluster-level criterion (PFWE-corrected<.05) based on the spatial extent and number of supra-threshold voxels (Puncorrected<.001).
Whole-brain investigation of sex and COMT-genotype effects
To widen the scope of the hypothesis-led region-of-interest (ROI) investigation, two exploratory whole-brain analyses were conducted to investigate the effects of sex, COMT-genotype and the interaction of these factors on activation during successful and failed inhibition trials respectively. Both analyses included 1133 participants. In each analysis the first-level contrast maps (for successful and failed inhibition respectively) were entered into a second-level random-effects analysis of variance (ANOVA) model to assess between-subject effects of sex and COMT-genotype. The effects of performance IQ (calculated as described in Methods) were accounted for with a regressor of no interest as performance IQ was seen to correlate with activation in the ROI analyses. Furthermore, dummy regressors for the eight sites of interest were included on account of previous investigation of data from the IMAGEN study, which demonstrated site differences in magnitude of activation (Tahmasebi et al, 2012). Significance was ascribed according to a cluster-level criterion (PFWE-corrected<.05) based on the spatial extent and number of supra-threshold voxels (Puncorrected<.001). In addition, to further scrutinise activation within the regions upon which this work is focused, small-volume correction was performed within the right-hemispheric pre-supplementary motor area (pre-SMA) and inferior frontal cortex (IFC) regions delineated in the ROI investigation. In these small-volume corrected regions significance was ascribed as above.
Correlates of stop-signal reaction time
Cerebral correlates of stop-signal reaction time (SSRT) during successful and failed inhibition were investigated in two further analyses carried out upon those subjects for whom SSRT could be estimated (n=630). These analyses were independent second-level random-effects ANOVA models on the first-level contrasts of successful and failed inhibition respectively, modelled to permit investigation of the effects of sex and COMT-genotype and accounting for the effects of performance IQ and site. In these analyses, however, a further covariate was included which denoted the individual-specific SSRT. Significance was ascribed according to a cluster-level criterion (PFWE-corrected<.05) based on the spatial extent and number of supra-threshold voxels (Puncorrected<.001) across the whole-brain and for the small-volume corrected pre-SMA and IFC regions.
Supplementary Results
Figure 2 depicts regions activated during successful and failed inhibition. Significant grey matter foci are presented in Table S8. Regions including bilateral IFC, pre-SMA, anterior insula and visual association cortices were significantly activated during both stop success and stop fail trials.
Widespread sex differences were noted during both successful and failed inhibition in the whole-brain analyses. These findings are presented in Tables S9 and S10, and in Figure S3. However, since investigation of sex differences in this work was constrained to those individuals for whom it was possible to establish COMT genotype, more explicit and expansive investigation of sex effects in the IMAGEN sample for this task will be reported (without this constraint) elsewhere.
The main effect of COMT-genotype or sex-by-COMT interaction produced no significant clusters at the whole-brain level. However, during both successful and failed inhibition elicited significant activation within the small-volume corrected region of the pre-SMA. These effects are presented in Tables S9 and S10.
SSRT positively predicted no significant clusters of activation for either trial type. A significant inverse relationship was found between SSRT and small-volume corrected activation in the pre-SMA during both successful and failed inhibition as is presented in Table S11.
Table S8. Grey-matter foci of activation during inhibition
Contrast / Region (Brodmann Area) / MNI coordinates / T-value / ClustersizeX / Y / Z
Stop success / Inferior parietal lobule (40) / -42 / -43 / 43 / 23.68 / 1088
Middle occipital gyrus (18) / 12 / -97 / 10 / 19.59 / 1088
Precuneus (7) / -21 / -64 / 52 / 13.69 / 1088
Lingual gyrus (18) / 3 / -85 / -8 / 11.97 / 1088
Middle frontal gyrus (6) / -48 / 2 / 37 / 14.11 / 1108
Precentral gyrus (6) / -42 / -4 / 49 / 11.66 / 1108
Caudate head / -15 / 17 / 1 / 7.05 / 1108
Inferior frontal gyrus (13) / 39 / 23 / 7 / 23.74 / 1108
Middle frontal gyrus (6) / 51 / 5 / 52 / 13.09 / 1108
Medial frontal gyrus (6) / 6 / 14 / 49 / 22.27 / 746
Middle frontal gyrus (10) / 39 / 59 / -5 / 8.61 / 509
Culmen / -36 / -52 / -35 / 10.79 / 123
Middle frontal gyrus (11) / -24 / 50 / -14 / 10.55 / 501
Middle frontal gyrus (46) / -45 / 38 / 34 / 10.52 / 501
Middle frontal gyrus (10) / -33 / 59 / -8 / 10.02 / 501
Superior frontal gyrus (10) / -42 / 53 / 22 / 6.78 / 501
Inferior temporal gyrus (20) / 45 / -1 / -38 / 9.78 / 38
Thalamus, ventral lateral nucleus / 9 / -10 / 7 / 8.78 / 85
Midbrain, red nucleus / 6 / -19 / -8 / 6.39 / 85
Midbrain, red nucleus / -3 / -22 / -8 / 6.69 / 44
Thalamus, medial dorsal nucleus / -9 / -22 / 10 / 6.40 / 44
Stop failure / Insula (13) / -33 / 17 / 7 / 30.84 / 1193
Middle frontal gyrus (6) / -48 / 2 / 37 / 13.55 / 1193
Inferior parietal lobule (4) / 51 / -40 / 49 / 19.65 / 4647
Middle occipital gyrus (18) / 12 / -97 / 10 / 15.93 / 4647
Inferior parietal lobule (40) / 60 / -43 / 28 / 15.54 / 4647
Culmen / 36 / -52 / -32 / 12.56 / 4647
Lingual gyrus (18) / 3 / -85 / -8 / 9.31 / 4647
Inferior frontal gyrus (47) / 33 / 20 / -8 / 16.53 / 982
Middle frontal gyrus (6) / 51 / 5 / 52 / 11.17 / 982
Medial frontal gyrus (6) / 3 / 14 / 52 / 21.83 / 882
Anterior cingulate gyrus (32) / 6 / 17 / 46 / 22.17 / 882
Inferior parietal lobule (40) / -45 / -43 / 43 / 21.55 / 1343
Culmen / -33 / -55 / -32 / 12.89 / 145
Inferior temporal gyrus (20) / 48 / -1 / -38 / 11.87 / 65
Thalamus, medial dorsal nucleus / 9 / -16 / 10 / 8.46 / 130
Midbrain, red nucleus / 6 / -19 / -8 / 6.45 / 130
Thalamus / -9 / -13 / 7 / 10.34 / 110
Thalamus, medial dorsal nucleus / -9 / -22 / 10 / 8.57 / 110
Midbrain, red nucleus / -6 / -22 / -8 / 7.53 / 110
Middle frontal gyrus (11) / -27 / 50 / -14 / 8.00 / 48
Middle frontal gyrus (10) / -33 / 59 / -8 / 7.18 / 48
Caudate body / 12 / 8 / 7 / 7.43 / 25
Middle frontal gyrus (11) / 24 / 50 / -14 / 7.02 / 62
Middle frontal gyrus (10) / 39 / 59 / -5 / 6.12 / 62
Middle frontal gyrus (10) / 45 / 53 / 1 / 4.92 / 62
Superior frontal gyrus (10) / 24 / 56 / 28 / 6.56 / 12
Table S9. Whole-brain effects of interest during successful inhibition. Asterisk denotes effects significant after small-volume correction.
Effect/Interaction / Region (Brodmann Area) / MNI coordinates / F-value / Cluster sizeX / Y / Z
Sex / Medial frontal gyrus (10) / 3 / 59 / 25 / 44.38 / 2366
Superior frontal gyrus (9) / -18 / 53 / 37 / 30.95 / 2366
Superior frontal gyrus (10) / 27 / 56 / -2 / 30.88 / 2366
Middle frontal gyrus (9) / -30 / 24 / 34 / 30.32 / 2366
Superior frontal gyrus (9) / -6 / 56 / 37 / 29.57 / 2366
Middle frontal gyrus (8) / 33 / 29 / 52 / 28.10 / 2366
Middle frontal gyrus (8) / 21 / 29 / 43 / 27.47 / 2366
Superior frontal gyrus (8) / 24 / 29 / 49 / 27.37 / 2366
Middle frontal gyrus (9) / 30 / 41 / 40 / 26.58 / 2366
Medial frontal gyrus (8) / -3 / 41 / 46 / 26.33 / 2366
Middle frontal gyrus (6) / -39 / 5 / 58 / 26.10 / 2366
Middle frontal gyrus (9) / -27 / 41 / 40 / 25.89 / 2366
Medial frontal gyrus (11) / -3 / 59 / -11 / 25.60 / 2366
Medial frontal gyrus (10) / 6 / 62 / 4 / 24.41 / 2366
Middle frontal gyrus (8) / -48 / 8 / 43 / 22.22 / 2366
Superior frontal gyrus (8) / -3 / 29 / 49 / 21.64 / 2366
Cingulate gyrus (24) / 15 / 5 / 49 / 21.37 / 2366
Precuneus (19) / -39 / -76 / 37 / 36.42 / 2715
Precuneus (7) / 3 / -55 / 37 / 34.93 / 2715
Precuneus (31) / -6 / -64 / 22 / 30.07 / 2715
Precuneus (7) / -6 / -58 / 46 / 29.87 / 2715
Angular gyrus (39) / -42 / -70 / 34 / 29.71 / 2715
Cingulate gyrus (32) / 3 / 11 / 46 / 28.53 / 2715
Precuneus (7) / 6 / -52 / 58 / 28.16 / 2715
Cingulate gyrus (31) / 3 / -55 / 25 / 27.93 / 2715
Superior occipital gyrus (19) / -36 / -82 / 28 / 26.83 / 2715
Paracentral lobule (3) / 18 / -40 / 58 / 25.95 / 2715
Precuneus (7) / 18 / -76 / 49 / 25.12 / 2715
Precuneus (7) / -6 / -64 / 55 / 23.24 / 2715
Postcentral gyrus (4) / 15 / -37 / 61 / 22.60 / 2715
Inferior parietal lobule (40) / -51 / -58 / 43 / 22.31 / 2715
Precuneus (7) / 6 / -76 / 49 / 22.27 / 2715
Precuneus (31) / -15 / -46 / 31 / 22.17 / 2715
Superior parietal lobule (7) / -27 / -79 / 43 / 21.92 / 2715
Superior temporal gyrus (39) / -57 / -58 / 28 / 21.64 / 2715
Precuneus (7) / 12 / -52 / 49 / 21.58 / 2715
Inferior frontal gyrus (45) / 54 / 23 / 7 / 35.62 / 294
Inferior frontal gyrus (45) / 57 / 20 / 19 / 21.69 / 294
Inferior frontal gyrus (47) / 48 / 26 / -11 / 17.49 / 294
Inferior frontal gyrus (45) / 51 / 35 / -2 / 14.46 / 294
Inferior frontal gyrus (9) / 57 / 20 / 28 / 14.25 / 294
Middle frontal gyrus (46) / 51 / 23 / 25 / 13.30 / 294
Inferior frontal gyrus (13) / -42 / 23 / 7 / 31.57 / 307
Inferior frontal gyrus (45) / -57 / 23 / 4 / 28.49 / 307
Inferior frontal gyrus (44) / -57 / 11 / 16 / 26.38 / 307
Inferior frontal gyrus (47) / -42 / 29 / -11 / 21.46 / 307
Inferior parietal lobule (40) / 51 / -61 / 40 / 16.91 / 285
Inferior parietal lobule (40) / 39 / -70 / 46 / 16.18 / 285
Middle temporal gyrus (21) / 45 / 2 / -35 / 29.89 / 109
Culmen / 0 / -64 / -8 / 25.57 / 210
Declive / -15 / -67 / -20 / 24.30 / 210
Declive / -6 / -76 / -17 / 23.77 / 210
Postcentral gyrus (3) / 54 / -13 / 46 / 22.15 / 110
Postcentral gyrus (2) / 54 / -25 / 49 / 15.61 / 110
Postcentral gyrus (2) / 48 / -31 / 43 / 13.52 / 110
Postcentral gyrus (4) / 45 / -16 / 55 / 11.98 / 110
Sex-by-COMT / Cingulate gyrus (32) / 12 / 20 / 46 / 11.12 / 5*
Cingulate gyrus (24) / 12 / 5 / 49 / 10.30 / 4*
Table S10. Whole-brain effects of interest during failed inhibition. Asterisk denotes effects significant after small-volume correction.
Effect/Interaction / Region (Brodmann Area) / MNI coordinates / F-value / ClustersizeX / Y / Z
Sex / Middle frontal gyrus (6) / -27 / 11 / 49 / 18.01 / 229
Middle frontal gyrus (8) / -45 / 8 / 46 / 16.21 / 229
Superior frontal gyrus (8) / -30 / 41 / 43 / 15.33 / 229
Posterior cingulate gyrus (31) / 6 / -58 / 22 / 28.01 / 943
Precuneus (31) / 15 / -64 / 28 / 27.22 / 943
Precuneus (7) / 3 / -61 / 34 / 26.78 / 943
Paracentral lobule (5) / -3 / -43 / 52 / 22.47 / 943
Precuneus (7) / 12 / -55 / 43 / 17.50 / 943
Precuneus (7) / 6 / -49 / 58 / 15.49 / 943
Precuneus (7) / -9 / -64 / 58 / 14.91 / 943
Precuneus (7) / -6 / -61 / 46 / 14.01 / 943
Precuneus (7) / 6 / -76 / 49 / 13.17 / 943
Precuneus (7) / 6 / -70 / 49 / 12.87 / 943
Paracentral lobule (5) / -15 / -37 / 52 / 11.57 / 943
Sex-by-COMT / Cingulate gyrus (32) / 12 / 5 / 49 / 10.48 / 5*
Table S11. Significant relationships between stop-signal reaction time and activation during inhibition. Clusters significant at whole-brain level, except where indicated by asterisk to denote small-volume corrected effects.
Contrast / Region (Brodmann Area) / MNI coordinates / T-value / Cluster sizex / y / z
Stop success / Superior frontal gyrus (6) / 6 / 5 / 67 / -3.43 / 2*
Stop failure / Superior frontal gyrus (6) / 6 / 8 / 64 / -3.95 / 19*
Superior frontal gyrus (6) / 9 / 11 / 70 / -3.38 / 19*
Figure S3. Plots of significant sex-effect foci, for stop success (left) in medial frontal gyrus (top; at MNI coordinates x=3, y=59, z=25), precuneus (middle; x=3, y=-55, z=27), and angular gyrus (bottom; x=-42, y=-70, z=34); and for stop failure (right) at middle frontal gyrus (top; x=-27, y=11, z=49), precuneus (middle; x=3, y=-61, z=34) and posterior cingulate gyrus (bottom; x=6, y=-58, z=22). All figures show group-averaged contrast estimates, and error bars signify 95% confidence intervals.
Supplementary Reference
Tahmasebi AM, Artiges E, Banaschewski T, Barker GJ, Bruehl R, Buchel C, et al (2012). Creating probabilistic maps of the face network in the adolescent brain: a multicentre functional MRI study. Hum Brain Mapp33(4): 938-957.