Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Sep;47(3):821-35.
doi: 10.1016/j.neuroimage.2009.05.043. Epub 2009 May 22.

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

Tor D Wager  1 , Christian E Waugh, Martin Lindquist, Doug C Noll, Barbara L Fredrickson, Stephan F Taylor
Affiliations

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

Tor D Wager et al. Neuroimage. 2009 Sep.

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.

PubMed Disclaimer

Figures

Figure 1
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
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 < .05 False Discovery Rate corrected, and contiguous regions at p < .005, are shown. B) Path b results for the first-level model (time series). Sagittal slices showing significant positive (yellow/orange) or negative (blue) correlates of heart rate changes over time, controlling for Speech Prep regressor. C) Path a results for the second-level model, showing correlations between SET-brain connectivity and HR reactivity. Positive correlations are shown in yellow, and negative correlation in blue. D) Path b results for the second-level model, showing correlations between brain-HRconnectivity and HR reactivity.
Figure 3
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 < .001 for display, but all regions showed significant effects in both paths at q < .05 FDR (p < .0004). The time series plots at right show group-averaged time series data across the run estimated with the Hierarchical Exponentially Weighted Moving Average (HEWMA) model. They are similar to, but smoother, than the raw data averages. Instruction periods are shown as yellow horizontal bars, and the Speech Prep period is shown as a blue horizontal bar in each plot. The HEWMA model provides estimates of which time points are deviant from the pre-SET baseline using a 2-state mixture model; these periods are marked with a red line. Time points that were individually significantly different from the average pre-scan baseline (zero on the y-axis) are marked with green dots at y = 0. The right (R) putamen alone showed evidence for a trend towards de-activation even before the speech instruction onset, as evidenced by a change-point value that occurred before the instruction. The right amygdala ROI showed significant de-activation in response to SET, but this activity did not predict heart rate fluctuations. Other amygdala sub-regions showed similar results.
Figure 4
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
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
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aguirre GK, Zarahn E, D'Esposito M. The Variability of Human, BOLD Hemodynamic Responses. Neuroimage. 1998;8(4):360–369. - PubMed
    1. Ahern GL, Sollers JJ, Lane RD, Labiner DM, Herring AM, Weinand ME, et al. Heart rate and heart rate variability changes in the intracarotid sodium amobarbital test. Epilepsia. 2001;42(7):912–921. - PubMed
    1. Al'Absi M, Bongard S, Buchanan T, Pincomb GA, Licinio J, Lovallo WR. Cardiovascular and neuroendocrine adjustment to public speaking and mental arithmetic stressors. Psychophysiology. 1997;34(3):266–275. - PubMed
    1. al'Absi M, Bongard S, Lovallo WR. Adrenocorticotropin responses to interpersonal stress: effects of overt anger expression style and defensiveness. Int J Psychophysiol. 2000;37(3):257–265. - PubMed
    1. Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, Maier SF. Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nat Neurosci. 2005;8(3):365–371. - PubMed

Publication types