BDNF Val66Met polymorphism tunes frontolimbic circuitry during affective contextual learning

Abstract

Adaptive learning impairments are common in cognitive and behavioral disorders, but the neurogenetic mechanisms supporting human affective learning are poorly understood. We designed a higher-order contextual learning task in which healthy participants genotyped for the Val66Met polymorphism of the brain derived neurotropic factor gene (BDNF) were required to choose the member of a picture pair most congruent with the emotion in a previously-viewed facial expression video in order to produce an advantageous monetary outcome. Functional magnetic resonance imaging (fMRI) identified frontolimbic blood oxygenation level dependent (BOLD) reactivity that was associated with BDNF Val66Met genotype during all three phases of the learning task: aversive and reward-predictive learning, contextually-challenging decision-making, and choice-related monetary loss-avoidance and gain outcomes. Relative to Val homozygotes, Met carriers showed attenuated ventromedial prefrontal response to predictive affective cues, dorsolateral prefrontal signaling that depended on decision difficulty, and enhanced ventromedial prefrontal reactivity that was specific to loss-avoidance. These findings indicate that the BDNF Val66Met polymorphism is associated with functional tuning of behaviorally-relevant frontolimbic circuitry, particularly involving the ventromedial prefrontal cortex, during higher-order learning.

Trial registration: ClinicalTrials.gov NCT00004571.

Published by Elsevier Inc.

Figures

Figure 1. Experimental Paradigm

The four events within each affective contextual learning trial. Red fixation crosses (500–820ms duration) indicate inter-stimulus intervals. (a) Affective video cues: sample still frames from videos (3000ms duration) of actors expressing fearful, happy and emotionally neutral facial expressions. (b) Decision-phase: following the fixation cross, through trial and error, participants learned to choose which of two pictures (top or bottom) was most emotionally congruent with the previously observed expression in (a). (c) a feedback condition reminding participants of their choice (circled in red); (d) monetary outcome phase: an outcome window showing participants the monetary outcome resulting from their choices. The outcome was programed to an 80% probability (i.e., 20% of the trials were invalid), in accordance with the emotion congruency matching rules. (b1 & b2) example feedback for an easy/low decision-load trial (b1) and for a difficult/high decision-load trial (b2).

Figure 2. BOLD Response to Predictive Affective Videos

(a) Main effect of emotional valence on regional representation of the predictive facial cues in supplementary motor area, superior frontal cortex, and medial vMPFC shown voxelwise and in a graph of values extracted from the a priori vMPFC ROI (see inset in 2b; F2, 58 = 4.6, p = 0.001). (b) Main effect of BDNF Val66Met polymorphism in the vMPFC shown voxelwise and for ROI results in the graph (F1, 59 = 7.363, p = 0.01); inserted brain image in graph shows the manually defined vMPFC ROI used throughout the analysis. (c) Interaction between affective learning context (passive viewing vs. affective learning) and valence (fear happy and neutral affective videos) was shown to influence vMPFC BOLD response such that the contextual learning caused more negative/decreased regional BOLD response, and more so in the neutral valence compared to passive affective viewing of the same cues (F1,31 = 28.15, p = 0.007). (d) Interaction between affective learning context (passive viewing vs. affective learning) and BDNF Val66Met genotype in an extended vMPFC region shown voxelwise and in a graph of values extracted from the vMPFC ROI shown in the inset; when the facial cues were predictive of aversive and rewarding outcomes, BDNF Met carriers, but not Val homozygotes, showed reduced vMPFC response (F1, 31 = 5.46, p = 0.026). Color bars represent F-statistics; voxelwise images shown at p < 0.005 for display and X, Y, Z coordinates are in MNI space.

Figure 3. BOLD Response during Affectively-Cued Picture Choices

(a) Behavioral performance (percent correct pictures choices): interaction between decision load and potential outcome valence (F2, 58 = 6.14, p = 0.004). (b) Main effect of load in the left orbitofrontal cortex shown voxelwise. (c) Interaction between load and BDNF Val66Met genotype in the DLPFC region during choice behavior shown voxelwise on a coronal slice, with the graph depicting values extracted from the DLPFC peak response: BDNF Met carriers showed increased DLPFC response when decisions were more difficult, and Val homozygotes showed the opposite pattern (F1, 59=12.93, p = 0.001). Color bars represent F-statistics; voxelwise images shown at p < 0.005 for display and X, Y, Z coordinates are in MNI space.

Figure 4. BOLD Response during Affectively-Cued Monetary Outcomes

(a) Interaction between monetary outcome type and BDNF Val66Met genotype in vMPFC shown voxelwise and in a graph of values extracted from the a priori vMPFC ROI: BDNF Met carriers responded most robustly to loss/avoidance-of-loss outcomes and least to neutral outcomes, whereas the pattern was opposite in Val homozygotes (F2, 58 = 6.49, p < 0.002). (b) Scatter-plot illustrating the correlation between vMPFC BOLD responsivity to predictive affective cues and DLPFC BOLD responsivity to choice picture cues (r = .352, p = 0.006). (c) the left scatter-plot illustrates the correlation between the vMPFC BOLD response to predictive affective cues and the end-point outcome cues (r = .445, p = 0.00033). The right scatter-plot illustrates the correlation between vMPFC BOLD outcome cues and performance on picture choices (r = .417, p = 0.001). Color bars represent F-statistics; voxelwise images shown at p < 0.005 for display and X, Y, Z coordinates are in MNI space.