Whole brain correlates of individual differences in skin conductance responses during discriminative fear conditioning to social cues

  1. Kevin Vinberg  Is a corresponding author
  2. Jörgen Rosén
  3. Granit Kastrati
  4. Fredrik Ahs
  1. Department of Psychology and Social Work, Mid Sweden University, Sweden
  2. Department of Psychology, Uppsala University, Sweden
  3. Department of Clinical Neuroscience, Karolinska Institutet, Sweden
8 figures, 7 tables and 1 additional file

Figures

Correlation between individual differences in conditioned SCR and whole brain responses during fear conditioning, obtained using individual SCR scores (Z transformed average CS+ minus CS- SCR) as a second level, between-subjects regressor of the average CS+ > CS- BOLD activation in SPM12 (Wellcome Department of Cognitive Neurology, University College, London) software.

The sample consisted of 285 participants who passed the following exclusion criteria: pregnancy, inability to lie still for a 1 hr duration, intolerance of tight confinements, ongoing psychological treatment, metal objects in the body (due to surgery, fragmentation, etc.), current alcohol or drug-related problems, use of psychotropic medications, unsuccessful recording of skin conductance responses, loss of brain imaging data due to excessive head movement, and participant failure to comply with task instruction regarding button press in at least 80% of trials. (A) Activation map of key implicated neural regions. Color-coded t values ranged from t = 3 to t = 6. The statistical image was thresholded at P < 0.05 FWE-corrected and displayed on an anatomical brain template. (B) Scatter plots depicting correlation between SCR difference scores and eigenvariates from significant whole brain clusters in the dorsal anterior cingulate cortex (upper panel) and the temporoparietal junction (lower panel). R = right dACC = dorsal anterior cingulate cortex. TPJ = temporoparietal junction. IFG = inferior frontal gyrus. PAG/RF = periaqueductal gray/reticular formation. AI = anterior insula.

Figure 1—source data 1

Variable data used to produce Figure 1B, Figure 2B and statistical analyses reported in the section ‘Relative contribution of neurofunctional correlates to individual differences in SCR’, as well as Appendix 1—figure 1, Appendix 2—figure 1 and Appendix 5—table 1.

Scatter plots depicting correlation between SCR difference scores and eigenvariates from significant neural regions were rendered using JASP version 0.14.1 (JASP Team, 2020). SCR source data was computed within the Ledalab software package (v 3.4.9; Benedek and Kaernbach, 2010) implemented in Matlab 2020a (Mathworks, Inc, Natick, MA) and individual SCR difference scores were computed using the JASP software (see Materials and methods, sections 4.2.4 and 4.3.2). fMRI source data was computed from the SPM software and extracted as eigenvariates from all significant clusters (see Materials and methods, section 4.3.3) and matched to the corresponding SCR difference scores in a comma separated values (CSV) file (attached). Within the attached file you can find SCR scores for each participant using both Z transformation and square root transformation, as well as average SCR responding to the CS+ and CS-, separately. Also included are extracted eigenvariates from all implicated regions in the whole brain analysis and the amygdala ROI analysis (section 2.2.2). Notice that this data also constitutes source data for Figure 2B as well as for statistical analyses reported in section 2.2.3 and for Appendix 1—figure 1, Appendix 2—figure 1, and Appendix 5—table 1.

https://cdn.elifesciences.org/articles/69686/elife-69686-fig1-data1-v2.csv
Correlations between individual differences in conditioned SCR and amygdala activation, obtained using individual SCR scores (Z transformed average CS+ minus CS- SCR) as a second level between-subjects regressor of the average CS+ > CS- BOLD activation in SPM12 (Wellcome Department of Cognitive Neurology, University College, London) software.

The sample consisted of 285 participants who passed the following exclusion criteria: pregnancy, inability to lie still for a 1 hr duration, intolerance of tight confinements, ongoing psychological treatment, metal objects in the body (due to surgery, fragmentation, etc.), current alcohol or drug-related problems, use of psychotropic medications, unsuccessful recording of skin conductance responses, loss of brain imaging data due to excessive head movement, and participant failure to comply with task instruction regarding button press in at least 80% of trials. (A) Activation map depicting significant activation on coronal section at MNI Y-coordinate = –2. Color-coded t values range from t = 2.0 to t = 4.0. The statistical image was thresholded at p < 0.05 FWE-corrected. (B) Scatter plot depicting correlation between SCR difference scores and eigenvariates from the significant right amygdala cluster within the amygdala ROI. For source data to (B), see Figure 1—source data 1.

Experimental setup.

Two male characters were displayed in the scanner during the fear conditioning task (top left, bottom right). One character predicted an electric shock (CS+) whereas the other served as a control stimulus and was never followed by shock (CS-). Between character presentations, participants viewed the empty virtual environment (top right, bottom left).

Appendix 1—figure 1
Histogram displaying distribution of SCR difference scores, defined as Z transformed average CS+ minus CS- SCR during a fear conditioning paradigm.

Sample consisted of 285 participants passing the following exclusion criteria: pregnancy, inability to lie still for a 1 hr duration, intolerance of tight confinements, ongoing psychological treatment, use of psychotropic medications, metal objects in the body (due to surgery, fragmentation etc.), current alcohol or drug related problems. For source data to Appendix 1—figure 1, see Figure 1—source data 1.

Appendix 2—figure 1
Histogram displaying distribution of average square root transformed raw value SCRs to the CS+ (left) and CS- (right) during a fear conditioning paradigm.

Sample consisted of 285 participants passing the following exclusion criteria: pregnancy, inability to lie still for a 1 hr duration, intolerance of tight confinements, ongoing psychological treatment, use of psychotropic medications, metal objects in the body (due to surgery, fragmentation etc.), current alcohol or drug related problems. For source data to Appendix 2—figure 1, see Figure 1—source data 1.

Appendix 3—figure 1
Correlation between individual differences in conditioned SCR and whole brain responses during fear conditioning, obtained using individual square root transformed raw value SCR scores (average CS+ minus average CS- SCR) as a second level between-subjects regressor of the average CS+ > CS- BOLD activation in SPM12 (Wellcome Centre for Human Neuroimaging, University College, London) software.

Sample consisted of 285 participants passing the following exclusion criteria: pregnancy, inability to lie still for a 1 hr duration, intolerance of tight confinements, ongoing psychological treatment, metal objects in the body (due to surgery, fragmentation etc.), ongoing substance abuse, use of psychotropic medications, unsuccessful recording of skin conductance responses, loss of brain imaging data due to excessive head movement, participant failure to comply with task instruction regarding button press in at least 80% of trials. Displayed is an activation map of key implicated neural regions. Color-coded t values ranges from t = 3 to t = 6. The statistical image was thresholded at p < 0.05 FWE-corrected and displayed on an anatomical brain template. dACC = dorsal Anterior Cingulate Cortex. TPJ = Temporoparietal Junction. IFG = Inferior Frontal Gyrus. PAG/RF = Periaqueductal gray/Reticular Formation. AI = Anterior Insula.

Appendix 4—figure 1
Correlation between individual differences in conditioned SCR and whole brain responses during fear conditioning with minimal participant exclusion.

Results obtained using individual SCR scores (Z transformed average CS+ minus CS- SCR) as a second level between-subjects regressor of the average CS+ > CS- BOLD activation in SPM12 (Wellcome Centre for Human Neuroimaging, University College, London) software. Sample consisted of 303 participants passing the following exclusion criteria: pregnancy, inability to lie still for a 1 hr duration, intolerance of tight confinements, ongoing psychological treatment, metal objects in the body (due to surgery, fragmentation etc.), ongoing substance abuse. Note that this is a larger sample than in the main analyses of the main text (n = 285), including an additional 5 participants with loss of brain imaging data due to excessive head movement, an additional 11 participants that failed to comply with the task instruction regarding button presses in at least 80% of trials and an additional 7 participants that used psychotropic medication. Displayed is an ctivation map of key implicated neural regions. Color-coded t values ranges from t = 3 to t = 6. The statistical image was thresholded at p < 0.05 FWE-corrected and displayed on an anatomical brain template. R = Right. dACC = dorsal Anterior Cingulate Cortex. TPJ = Temporoparietal Junction. IFG = Inferior Frontal Gyrus. PAG/SC = Periaqueductal gray/Superior Colliculus. AI = Anterior Insula.

Appendix 6—figure 1
Whole brain CS+ > CS- BOLD contrast activations during a fear conditioning paradigm.

Results obtained using first-level event-related modeling of conditioned and unconditioned stimuli in a general linear model predicting BOLD signal and then examining the overall whole brain CS+ > CS- BOLD contrast on the group level in SPM12 (Wellcome Centre for Human Neuroimaging, University College, London). Sample consisted of 285 participants passing the following exclusion criteria: pregnancy, inability to lie still for a 1 hr duration, intolerance of tight confinements, ongoing psychological treatment, metal objects in the body (due to surgery, fragmentation etc.), ongoing substance abuse, use of psychotropic medications, unsuccessful recording of skin conductance responses, loss of brain imaging data due to excessive head movement, participant failure to comply with task instruction regarding button press in at least 80% of trials. Color-coded t values ranges from t = 4.0 to t = 20. Statistical images are thresholded at p < 0.05 FWE-corrected. Abbreviations: dACC = dorsal anterior cingulate cortex; VS = ventral striatum; SMA = supplementary motor area; Pre-SMA = pre-supplementary motor area; dPrec = dorsal precuneus; MCC = midcingulate cortex; Thal = thalamus; dPons = dorsal pons; AIC = anterior insula cortex; MTG = medial temporal gyrus; MOG = medial occipital gyrus; mPFC = middle prefrontal cortex; MFG = middle frontal gyrus; IFG = inferior frontal gyrus; SMG = supramarginal gyrus.

Tables

Table 1
Previous studies examining the association between individual differences in skin conductance responses (SCR) and neural activation during fear conditioning.
StudyParticipants (n)AnalysisDefinition of individual SCR scoresDefinition of neural activationROI(s)Statistical thresholdFindings
LaBar et al., 19985CorrelationCS+ minus CS-No. of voxels in
CS+ > CS- contrast
Amygdala, rostral and caudal ACCPUnc < 0.001Positive correlation in Amygdala
Phelps et al., 200411CorrelationCS+ minus CS-CS+ > CS- contrastAmygdala, mid PFCPUnc < 0.001Positive correlation in Amygdala
Dunsmoor et al., 201114CorrelationCS+ minus CS-CS+ > CS- contrastWhole brain, AmygdalaWhole brain: PUnc < 0.001 then ROI: PFWE < 0.05Positive correlation in left Amygdala
Petrovic et al., 200827CorrelationLate(CS+ minus CS-) - Early(CS+ minus CS-)CS+ > CS- contrastAmygdala, Fusiform Gyrus and pain regions from Peyron et al., 2000PUnc < 0.001Positive correlation in Amygdala
MacNamara et al., 201549CorrelationCS+ minus CS-CS+ > CS- contrastAmygdala, Insula, ACC, cerebellum (lobule 4–5), mPFC, precentral gyrus, STGPUnc < 0.001 then PFWE < 0.05 using ClusterSimPositive correlation in right Amygdala and left SMA. Positive correlation in left Amygdala using relaxed statistical threshold.
Marin et al., 202060High vs. low SCR responders (drawn from larger sample of N = 109)CS+ minus CS-CS+ > CS- contrastAmygdala, Insula, dACC, sgACC, vmPFCCombined ROIs: PUnc < 0.001; Single ROIs: PFWE < 0.05High SCR responders > Low responders: Left Amygdala, left Insula and vmPFC
  1. Note: ACC, Anterior cingulate cortex; dACC, dorsal ACC; FWE, Family-wise error, mPFC, medial PFC; PFC, Prefrontal cortex; sgACC, subgenual ACC; Unc, Uncorrected; vmPFC, ventromedial PFC.

Table 2
Whole brain correlation to conditioned SCR.
Anatomical regionHemisphereVoxelstMNI Coordinates
xyz
Dorsal Anterior Cingulate Cortex/Anterior Midcingulate CortexN/A504.796840
Anterior InsulaRight204.6536206
Inferior Frontal Gyrus/Frontal OperculumRight1385.8056102
Temporoparietal Junction/Superior Temporal GyrusRight815.6664–4020
Superior Frontal Gyrus/Dorsal Premotor CortexRight445.2118068
MidbrainRight595.2210–30–12
Superior Parietal Lobe/Postcentral GyrusRight34.5222–4670
Superior Frontal Gyrus/Dorsal Premotor CortexLeft24.46–14-272
Temporoparietal Junction/Superior Temporal GyrusLeft14.37–62–3622
  1. Note. MNI coordinates and t values represent significant peak voxels of each cluster. Statistical significance was calculated using t tests implemented within the SPM software with an FWE corrected alpha level of α = .05.

Appendix 3—table 1
Whole Brain Correlation to Conditioned SCR using square root transformed raw value SCR.
Anatomical regionHemisphereVoxelstMNI Coordinates
xyz
Dorsal Anterior Cingulate Cortex/Anterior Midcingulate CortexN/A214.584840
Anterior InsulaRight184.6036226
Inferior Frontal Gyrus/Frontal OperculumRight1445.6656122
Temporoparietal Junction/Superior Temporal GyrusRight1165.6464–4020
Superior Frontal Gyrus/Dorsal Premotor Cortex/Supplementary Motor AreaRight1255.5416066
MidbrainRight615.036–30–10
Temporoparietal Junction/Superior Temporal GyrusLeft64.49–62–3622
  1. Note. MNI coordinates and t values represent significant peak voxels of each cluster. Statistical significance was calculated using t tests implemented within the SPM software with an FWE corrected alpha level of α = .05.

Appendix 4—table 1
Whole Brain Correlation to Conditioned SCR without participant exclusion (N = 303).
Anatomical regionHemisphereVoxelstMNI Coordinates
xyz
Dorsal Anterior Cingulate Cortex/Anterior Midcingulate CortexN/A1015.0661038
Anterior InsulaRight164.5436206
Inferior Frontal Gyrus/Frontal OperculumRight1495.6756102
Temporoparietal Junction/Superior Temporal GyrusRight915.8264–4020
Superior Frontal Gyrus/Dorsal Premotor Cortex/Supplementary Motor AreaRight174.7218068
MidbrainRight745.2910–32–10
Inferior frontal gyrusLeft24.35–5602
  1. Note. MNI coordinates and t values represent significant peak voxels of each cluster. Statistical significance was calculated using t tests implemented within the SPM software with an FWE corrected alpha level of α = .05.

Appendix 5—table 1
Beta coefficients from regression model.
ModelUnstandardizedStandard ErrorStandardizedtp
H₀(Intercept)0.6420.02823.284<.001
H1(Intercept)0.4340.0449.773<.001
R IFG0.0880.0860.1051.0260.306
R TPJ0.1360.0880.1331.5510.122
R Midbrain0.1780.1070.1221.6710.096
R dPMC0.0770.1050.0650.7330.464
dACC–0.0640.092–0.072–0.6990.485
R AI0.0000.0800.0000.0110.992
R SPL0.0390.0620.0470.6180.537
L SFG0.0790.0850.0750.9390.349
L TPJ–0.0110.070–0.013–0.1620.872
  1. Note. Coefficient results obtained from regression analysis within the JASP software (JASP Team (2020). JASP (Version 0.14.1) [Computer software]) using eigenvariates from implicated whole brain regions as independent regressors of individual differences in conditioned SCR. Abbreviations: R = Right; L = Left; TPJ = Temporoparietal Junction; IFG = Inferior Frontal Gyrus; dACC = dorsal Anterior Cingulate Cortex; dPMC = dorsal Premotor Cortex; AI = Anterior Insula; SPL = Superior Parietal Lobe.

Appendix 6—table 1
Whole brain CS+ > CS- BOLD contrast activations.
ClusterBrain regions with peaks within clustertPeak MNI Coordinates
xyz
Cluster 1 (46343 voxels): insula, ventral striatum, inferior, middle and superior frontal cortex, thalamus, midbrain/brainstem, anterior and midcingulate cortex, supplementary motor area, middle and superior temporal gyri, supramarginal gyrus, inferior and superior parietal cortex, amygdala, cerebellum.-> 4.34---
Right Insula21.7136242
Left Insula18.71–3224-4
Left Insula17.55–4018-4
Right Frontal Operculum17.065662
Supplementary Motor Area19.244650
Supplementary Motor Area/Midcingulate Cortex19.212846
Right Caudate18.351064
Left Caudate17.20–1062
Thalamus20.104–24-2
Right Temporoparietal Junction17.8650–3220
Right Precentral Gyrus16.2946246
Cluster 2 (217 voxels): Right Cuneus
Right Cuneus8.4614–7238
Cluster 3 (208 voxels): Left Middle Prefrontal Cortex
Left Middle Prefrontal cortex6.33–384624
Cluster 4 (69 voxels): Left Cuneus, Left Posterior PrecuneusLeft Posterior Precuneus6.04–10–7438
Cluster 5 (61 voxels): Left dorsal Cerebellum, Left Fusiform GyrusLeft Cerebellum VI5.61–34–60–26
Left Cerebellum VI5.05–38–64–24
Left Fusiform Gyrus5.00–40–66–20
Left Cerebellum VI4.45–38–54–26
Cluster 6 (15 voxels): Right Visual CortexRight Visual Cortex4.9620–646
Cluster 7 (9 voxels): Left Visual CortexLeft Visual Cortex4.69–14–704
Cluster 8 (8 voxels): Right Frontal Pole/Superior Orbital GyrusRight Frontal Pole4.562660-6
  1. Note. MNI coordinates and t values represent significant peak voxels within each cluster. Statistical significance was calculated using t tests with an FWE corrected alpha level of α = .05 within the SPM software.

Appendix 7—table 1
Sensitivity analysis.

Correlations to conditioned SCR in the significant peak voxels from the main analysis altering SCR definitions, covariates, and sample selection. Pearson correlation coefficients (r) were included to permit comparison of effect sizes. Main analysis refers to the analysis presented in the results section of the paper. Square-root transformed refers to using square-root transformed Z-transformed SCRs. The PsPM analysis used a model-based approach to compute SCR based on a Dynamic Causal Modeling framework. Please notice that this model may not be optimally suited to our data, see Appendix 8 for more information. 5 s SCR window used 5 s time window following CS-onset for peak-detection. Non-reinforced trials only included non-reinforced CS+ trials when computing SCR and neural responses. To control for shock expectancy effects, we included average shock expectancy (rated online as 0 or 1) as a covariate correlating with whole-brain responses. We also controlled for eventual familial influences by splitting twin pairs and correlating SCR in the two samples (first twin, second twin) to brain contrast values. Note that the full sample included twin pairs as well as twins without a sibling, hence there is a discrepancy in the number of twins for first and second columns (135 vs 146). Correlations between SCR to US and CS+ > CS- contrast-values are shown in the last column for reference.

Anatomical regionHemisphereVoxelsxyzMain analysisSquare-root transformedPsPM (DCM) analysis5 s SCR time-windowNon-reinforced trialsControl for shock expectancyExcluding first twinExcluding second twinSCR to US
t283 (r)t283 (r)t283 (r)t283 (r)t283 (r)t282 (r)t135 (r)t146 (r)t283 (r)
Dorsal Anterior
Cingulate Cortex/
Anterior Midcingulate
Cortex
N/A5068404.79(0.27)4.58(0.26)3.63(0.21)4.95(0.28)4.55(0.26)3.07(0.18)3.90(0.32)2.78(0.23)0.00(0.00)
Anterior InsulaRight20362064.65(0.27)4.50(0.26)4.51(0.26)5.01(0.29)3.95(0.23)2.69(0.16)3.68(0.30)2.88(0.24)0.31(0.02)
Inferior Frontal
Gyrus/Frontal
Operculum
Right138561025.80(0.33)5.31(0.30)5.03(0.29)5.94(0.33)5.02(0.29)3.44(0.20)4.69(0.37)3.59(0.30)1.35(0.08)
Temporoparietal
Junction/Superior
Temporal Gyrus
Right8164–40205.66(0.32)5.45(0.31)4.39(0.25)5.68(0.32)4.49(0.26)3.54(0.21)4.22(0.34)3.81(0.31)1.44(0.09)
Superior Frontal
Gyrus/Dorsal
Premotor Cortex
Right44180685.21(0.30)5.25(0.30)4.12(0.24)5.20(0.30)4.73(0.27)2.58(0.15)3.70(0.30)3.65(0.30)0.91(0.05)
MidbrainRight5910–30–125.22(0.30)5.14(0.29)5.06(0.29)5.03(0.29)4.53(0.26)2.78(0.16)4.00(0.33)3.31(0.27)2.51(0.15)
Superior Parietal
Lobe/Postcentral
Gyrus
Right322–46704.52(0.26)4.28(0.25)3.89(0.23)4.97(0.28)4.30(0.25)2.89(0.17)3.51(0.29)2.86(0.24)1.81(0.11)
Superior Frontal
Gyrus/Dorsal
Premotor Cortex
Left2–14-2724.46(0.26)4.39(0.25)4.12(0.24)4.71(0.27)4.45(0.26)3.05(0.18)4.52(0.36)2.00(0.17)0.56(0.03)
Temporoparietal
Junction/Superior
Temporal Gyrus
Left1–62–36224.37(0.25)4.24(0.24)3.02(0.18)5.07(0.29)3.93(0.23)1.81(0.11)3.73(0.31)2.55(0.21)1.65(0.10)
  1. Note. MNI coordinates and t values represent significant peak voxels of clusters from the main analysis. Statistical significance was calculated using t tests implemented within the SPM software with an FWE corrected alpha level of α = .05.

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  1. Kevin Vinberg
  2. Jörgen Rosén
  3. Granit Kastrati
  4. Fredrik Ahs
(2022)
Whole brain correlates of individual differences in skin conductance responses during discriminative fear conditioning to social cues
eLife 11:e69686.
https://doi.org/10.7554/eLife.69686