+ How negative do you feel? 2 sec 4 sec 8 sec 4 – 7 sec2.1 sec4 – 7 sec Anticipation and Stimulus Trial + + Figure 1 Columbia Psychology SCAN Unit INTRODUCTION METHODS PARTICIPANTS n = 36 participants, mean age = 22 years SCAN & ANALYSIS PARAMETERS EPI BOLD imaging on 1.5T GE (TR = 2 s, 31 slices 3.5 x 3.5 x 4.5 mm voxels). Pre-processing and 1st level analysis with SPM2 2nd-level analysis using MEPM toolbox (beta version available from ) STIMULI Negative and neutral images from the Int’l Affective Picture System (IAPS) TRIAL TYPES Reappraise Negative Images = Instructed regulation Look at Negative Images = Spontaneous responses, which could include regulation of emotion Look at Neutral Images = Spontaneous responses to neutral events TRIAL STRUCTURE BACKGROUND The capacity to adaptively regulate emotion is essential for both mental and physical health. Recent imaging research has identified regions of PFC important for the goal-directed reappraisal of aversive stimuli (Beauregard et al., 2001; Ochsner et al., 2002; Phan et al., 2004; Urry et al., 2006) These studies have identified both cortical and subcortical activation related to cognitive reappraisal of emotion, but they have not systematically identified cortical-subcortical pathways. QUESTION In this study, we sought to investigate cortical-subcortical pathways that predict self-reported reappraisal success. We used a novel strategy of mediation effect parametric mapping (MEPM) to locate subcortical mediators of observed prefrontal- reappraisal success relationships. (see also posters A125 and B95) RESULTS SUMMARY and CONCLUSIONS Step 1: Bilateral VLPFC and other prefrontal regions are correlated with reported success when reappraising aversive pictures. Step 2: The relationship between VLPFC activity and success is mediated by statistically separable pathways through amygdala and NAC. Activation of the amygdala pathway predicts lower reappraisal success (more negative emotion), and activation of the NAC pathway predicts greater success. VLPFC is positively associated with both pathways, implying a role in both up- and down-regulation of emotion by appraisal. Step 3: Two separate networks of mediators connected to VLPFC were found. The positive mediation network involved NAC, pre-SMA, retrosplenial cortex and precuneus, and was associated with greater success. The negative mediation network involved rostral, dorsal cingulate, amgydala, subthalamus, and pons, and was associated with lower success. Step 4: Several other frontal regions, including dorsal and ventral medial PFC, also showed relationships with reappraisal success mediated by NAC. However, only right VLPFC and orbitofrontal cortex showed relationships with success mediated by amygdala. REFERENCES ANALYSIS PATHWAY Step 1 Identify prefrontal seed region of interest. Used contrasts to identify regions involved in instructed reappraisal (Reapp Neg > Look Neg) that were a) activated and b) correlated positively with reappraisal success. Defined right VLPFC as prefrontal seed region. Step 2 Test pathways in subcortical regions of interest. Defined regions of interest around amygdala and ventral striatum/nuc. Accumbens (NAC). Conducted mediation analyses (MEPM) for voxels in these regions. See Step 2 Hypotheses at right. Step 3 Identify additional mediators and functional networks to which they belong. Purpose: “Big picture” understanding of networks constrains inference. Performed MEPM analysis over whole brain, searching for other mediators. Used hierarchical clustering and permutation test to group regions into networks, and examine mediation on network averages. Step 4 Identify additional prefrontal regions mediated by amygdala and NAC. Purpose: Move beyond single prefrontal ROI to examine “big picture” in frontal cortex. Identified regions involved in both spontaneous and instructed regulation (P <.1 FDR activation and p <.05 correlation in 1 AND 2) See Poster I 64 for a summary of neuroimaging studies of reappraisal Ochsner, K. N., Bunge, S. A., Gross, J. J., & Gabrieli, J. D. E. (2002). Rethinking feelings: An fMRI study of the cognitive regulation of emotion. Journal of Cognitive Neuroscience, 14:8. Mediation analyses of VMPFC-amygdala relationship: (see also work by M. Lieberman): Urry, H. L., van Reekum, C. M., Johnstone, T., Kalin, N. H., Thurow, M.E., Schaefer, H. S., et al. (2006). Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults. JNeurosci, 26(16), Meta-analysis showing brain regions that predict valence of emotional experience: Wager, T. D., Barrett, L. F., Bliss-Moreau, E., Lindquist, K., Duncan, S., Kober, H., et al. (in press). The Neuroimaging of Emotion. In M. Lewis (Ed.), Handbook of Emotion. See also posters A125 and B95 for more on mediation effect parametric mapping See also posters C12, I64, I59, D39 for more on brain representation of emotion Download this poster: Download this poster: Unpacking prefrontal function in emotion regulation: fMRI evidence for independent functional pathways through amygdala and nucleus accumbens Tor D. Wager 1, Matthew Davidson 1, Brent Hughes 2, Martin A. Lindquist 3, and Kevin N. Ochsner 1 1 Department of Psychology, Columbia University; 2 Department of Psychology, University of Texas; 3 Department of Statistics, Columbia University Figure 1 Mediators: Which brain regions? Reappraisal Success (Drop in reported negative experience) Control system Activity (Right vlPFC) Direct Path c’ Indirect Path a Indirect Path b Question 1: Does activity in subcortical “affective appraisal systems” mediate the vlPFC- experience relationship? Mediation Hypothesis: If yes, paths a, b, and their product a*b should be significant Direct pathway Hypothesis: No, only direct path c’ is significant Question 2: If there is mediation, what type of appraisal system does it involve? Negative Mediation: Systems involved in negative affect, like the amygdala Positive Mediation:Systems involved in positive affect, like the striatum Multiple mediation: Multiple, statistically independent mediating regions q <.01 FDR, P <.0004 P <.001 q <.05 FDR, P <.0046 Color key Whole-brain search +- P <.005 P <.01 P <.05 Color key Constrained search +- Activated regions [Reappraise Negative - Look Negative] Regions within active area correlated with reappraisal success VLPFC (R) AMY (L) NAC (L) Reappraisal Success [Neg - Rea] 0.42 (0.15)** 0.18 (0.09)* 0.57 (0.17)*** (0.06)*** Direct: 0.19 (0.06)* VLPFC (R) Reappraisal Success [Neg - Rea] 0.66 (0.08)*** Total: 0.15 (0.08)* Direct: 0.24 (0.09)* Path a1 Path b (0.08)*** Path b (0.18)*** Path a (0.11)** Path b1 Path b2 a1*b1 distribution a2*b2 distribution Network avg. [Rea - Neg] a1*b1 value a2*b2 value Reappraisal Success Pre-SMA vStr and sgACC Amygdala rdACC Mediators of VLPFC-Reappraisal Success connectivity Amygdala Hippocampus Caudate Thalamus Pre-SMA SFS Precuneus CIs vaIns CIs Amy sgACC vStr sgACC SFS Pre-SMA Precuneus NAC/ sgACC CIs rdACC Amy, vaIns Path model with networks as mediators Subthal. Zone, vPons Step 1 Identify prefrontal seed region of interest Chosen Seed region MEPM analysis in general: Specify two of the three variables in the path model below Search the third variable over brain voxels, making parametric maps of each effect Bootstrap test provides nonparametric inference The Mediation Effect Parametric Map analysis, and application to reappraisal data MEPM analysis in this case: Specify prefrontal seed (predictor) and reappraisal success (outcome) Search for brain areas in which [Reappraise - Look Negative] mediates the prefrontal activity- success relationship r = 0.68, t = 4.22, p = r = 0.62, t = 3.78, p = VLPFC (L)VLPFC (R) Prefrontal Seed region Regions of Interest NAC Amy Step 2 Test pathways in subcortical regions of interest Significant mediators, and path model with both included together Histogram of bootstrapped Mediation (a*b) effects VLPFC (L)VLPFC (R) DMPFC (BA 9) MFP (BA 10/32) VMPFC/MOFC (BA 25/11) MOFC LOFC VLPFC (R) SGACC MFP (BA 10/32) DMPFC VMPFC SFS FROP Pre-SMA Amygdala Reappraisal Success Which regions? Nuc. accumbens Reappraisal Success Which regions? Step 3 Identify additional mediators and functional networks Step 4 Identify additional prefrontal regions mediated by amygdala and NAC * = p <.05, ** = p <.01; ***, p <.001, two-tailed NAC Mediation effect: Significant product of a*b paths. Interpretation: inclusion of indirect path significantly affects predictor-outcome relationship Cognitive & Affective Control Lab * Download this poster at the website above * Also: Software, results,meta-analysis ROIs