Connectivity Analysis (Psychophysiological Interaction): Methods

Supplementary Material

Connectivity analysis (Psychophysiological Interaction): Methods

The seed region of the PPI analysis was based on a task by group interaction (group differences for the contrast ‘uncued compared to cued negative minus neutral pictures’). Therefore, group differences in connectivity which may be explained by group effects of the task have to be controlled for. In the analysis reported in the manuscript, this was accomplished by including the task conditions as regressors into the PPI single subject’s analysis.

To further control for group differences of the task that may be affecting variance in the seed time course an additional PPI analysis was performed. In this new PPI analysis, the seed time courses were re-extracted. The variance of the time series accounted for by task related effects was now removed from the seed time courses by using the adjustment function of SMP 5. Again, to create the Psychophysiological Interaction (PPI) term the time series of the cortical seed region (e.g. the BA10) was extracted and deconvolved within a Bayesian framework to generate the neuronal signal for the seed region. As seed region the peak voxel of the group effect for ‘uncued compared to cued negative minus neutral pictures’ was chosen
(x/y/z=-12/60/3). The set up of the first level statistical models equaled the previously reported procedures (see methods section PPI). Group, genotype and group-by-genotype effects were again assessed with a two-sample t-test with the genotype added as covariate implicating 5-HTT low expression allele count (0, 1 or 2).

Connectivity analysis (Psychophysiological Interaction): Results

Results of the adjusted PPI analysis resembled the original analysis results: Significantly increased connectivity between the mPFC (BA 10) and bilateral amygdala in short allele carriers among healthy controls > MDD patients for uncued aversive pictures (left amygdala: x/y/z = -18/0/-12, T=4.23, p=0.004 FWE corrected; right amygdala x/y/z = 18/3/-18, T=2.94, p=0.038 FWE corrected).

5-HTT-genotype effect on amygdala activation in negative minus baseline and neutral minus baseline negative pictures: Results

With respect to previous findings (Canli et al. 2005, Heinz et al. 2007) we also assessed genotype modulated amygdala activation for the contrasts negative minus baseline (fixation cross) which also revealed a tendency for genotype-dependent amygdala activation across both groups in the right amygdala (x/y/z=18/3/-18, T=2.37, p=0.097), whereas the group-by-genotype interaction remained significant for stronger genotype-modulated amygdala response in MDD compared to HC (left amygdala x/y/z=-30/0/-27, T=3.76, p=0.004, right amygdala: x/y/z= 24/-9/-12, T=3.6, p=0.006) (Supplementary Fig 1a). We did not observe genotype modulated amygdala activation, nor group-by-genotype interaction for neutral minus baseline negative pictures (p>0.1) (Supplementary Fig 1b).

Supplementary Figure 1

A. Parameter estimates of bilateral amygdala activation plotted against 5-HTT genotype for s-allele carriers (sX) vs. homozygous LALA-allele carriers (again with respect to the A<G exchange, LG variants were treated like s-alleles) for the contrast negative minus baseline (fixation cross) in healthy controls (HC) and patients with Major Depression (MDD)

B. Parameter estimates of bilateral amygdala activation plotted against 5-HTT genotype for s-allele carriers (sX) vs. homozygous LALA-allele carriers (again with respect to the A<G exchange, LG variants were treated like s-alleles) for the contrast neutral minus baseline (fixation cross) in healthy controls (HC) and patients with Major Depression (MDD)

Supplementary References

Canli, T., Omura, K., Haas, B. W., Fallgatter, A., Constable, R. T. and Lesch, K. P. (2005) Beyond affect: a role for genetic variation of the serotonin transporter in neural activation during a cognitive attention task. Proceedings of the National Academy of Sciences of the United States of America 102, 12224-12229.

Heinz, A., Smolka, M.N., Braus, D.F., Wrase, J., Beck, A., Flor, H., Mann, K., Schumann, G.,

Büchel, C., Hariri, A.R., Weinberger, D.R. (2007) Serotonin transporter genotype (5-HTTLPR): effects of neutral and undefined conditions on amygdala activation. Biol Psychiatry 61, 1011-1014.