Brain mediators of cardiovascular responses to social threat: part I: Reciprocal dorsal and ventral sub-regions of the medial prefrontal cortex and heart-rate reactivity

Abstract

Social threat is a key component of mental "stress" and a potent generator of negative emotions and physiological responses in the body. How the human brain processes social context and drives peripheral physiology, however, is relatively poorly understood. Human neuroimaging and animal studies implicate the dorsal medial prefrontal cortex (MPFC), though this heterogeneous region is likely to contain multiple sub-regions with diverse relationships with physiological reactivity and regulation. We used fMRI combined with a novel multi-level path analysis approach to identify brain mediators of the effects of a public speech preparation task (social evaluative threat, SET) on heart rate (HR). This model provides tests of functional pathways linking experimentally manipulated threat, regional fMRI activity, and physiological output, both across time (within person) and across individuals (between persons). It thus integrates time series connectivity and individual difference analyses in the same path model. The results provide evidence for two dissociable, inversely coupled sub-regions of MPFC that independently mediated HR responses. SET caused activity increases in a more dorsal pregenual cingulate region, whose activity was coupled with HR increases. Conversely, SET caused activity decreases in a right ventromedial/medial orbital region, which were coupled with HR increases. Individual differences in coupling strength in each pathway independently predicted individual differences in HR reactivity. These results underscore both the importance and heterogeneity of MPFC in generating physiological responses to threat.

Figures

Figure 1

A) Task design. The SET manipulation involved a 2-min resting baseline, a 15 sec visual presentation of the speech topic, a 2-min preparation period, a 15-sec no speech instruction, and a 2.5 min recovery period. B) Nuisance regressors for fMRI analysis. These varied across participants, but always included regressors for linear and higher-order head movement, potential outliers based on task- and physiology-blind global signal analysis, global activity values, and linear drift. C) Heart rate changes over time. Individuals are shown by the light gray lines, and the group average (with shaded standard error region) is shown by the heavy black line.

Figure 2

Path model (top) and results of the multi-level mediation effect parametric mapping search. Relationships between Speech Prep and brain activity (Path a) and between fMRI activity and heart rate (Path b, controlling for the Speech Prep regressor) were tested both within person and between persons, with heart rate (HR) reactivity as a predictor of individual differences in path amplitude. A) Path a results for the first-level model (time series). Saggital slice showing regions whose activity increased (yellow/orange) or decreased (blue) in response to the social evaluative threat (SET) challenge. Significant regions of 3 or more contiguous voxels at q

Figure 3

Regions showing both Path a (SET responses) and Path b (prediction of HR) in the first-level (time series) model, and results from one amygdala region of interest (ROI). Positive results for both Path a and Path b are shown in red, and negative results for both are shown in blue. No regions showed positive a and negative b effects or vice versa. Results are shown at P

Figure 4

Visualization of brain-HR connectivity (related to Path b) for the pregenual cingulate. A) Superimposed plots of the group-average time series data (black, with standard error regions shaded) against the group-average HR data (red). Speech Prep-related variance was not removed for display purposes, so the response to the social threat challenge can be seen. In addition, nuisance covariates (see Figure 1C) were not removed for display purposes, so the original response in both brain and heart can be seen. Only standard preprocessing procedures were performed. Instruction periods are shown as yellow horizontal bars, and the Speech Prep period is shown as a blue horizontal bar. B) The same plot as in (A), but with nuisance covariates removed. C) Plots of brain (black) and superimposed HR (red) for individual subjects, each shown in a separate panel.

Figure 5

Path diagram and effect plots for the pregenual anterior cingulate (pgACC). A) Path a results for Level 1 (time series SET-brain relationship) and Level 2 (correlation between SET-brain relationship and HR reactivity). Cross-hairs indicate center-of-mass coordinates for the SET effect (Path a, blue) and heart-rate prediction effect (Path b, green). Mean path coefficients are shown, with standard errors in parentheses. ***, P < .001. The line plot (left panel) shows the first-level effects, the relationships between the SET predictor (which took on values of 0 for baseline and 1 during speech preparation; x-axis) and fMRI activity (y-axis). Relationships for Individual participants are shown as blue lines, one per participant. The group-average effect with its standard error is shown by the black line and gray shaded area. The right panel shows a scatterplot of the second-level relationship between individual differences in the slope of the Path a effect (x-axis) and the average HR response to the task (y-axis). The significant relationship (r = .68, p < .00037 [the FDR threshold]) indicates that those with high HR reactivity showed larger SET-brain (Path a) effects. B) The same relationships for the brain-HR relationship (Path b), controlling for the SET predictor. Significant first- and second-level effects demonstrate the reliable link between individual profiles of brain activity and individual profiles of HR changes across time.

Figure 6

Mediation path diagram for all three key mediators of social evaluative threat (SET) effects on heart rate. Solid black lines indicate significant relationships, and light gray lines indicate non-significant relationships. Connections hypothesized to be directional are shown as one-way arrows, whereas effects likely to be bi-directional (feedback loops) based on anatomy are shown as double-headed arrows. Causality could only be inferred for the SET-brain effects because SET was experimentally manipulated. First-level effects (SET-brain connectivity for Path a or brain-HR connectivity for Path b) are shown as line plots, and second-level effects (correlations between Path a or Path b and HR reactivity) are shown as scatterplots. Effect plots are shown for pregenual cingulate (pgACC) and medial orbitofrontal cortex (mOFC), but are omitted for putamen (Put) for space reasons. Full statistics are presented in Table 5.