Functional connectivity between the amygdala and prefrontal cortex underlies processing of emotion ambiguity.

Processing facial expressions of emotion draws on a distributed brain network. In particular, judging ambiguous facial emotions involves coordination between multiple brain areas. Here, we applied multimodal functional connectivity analysis to achieve network-level understanding of the neural mechanisms underlying perceptual ambiguity in facial expressions. We found directional effective connectivity between the amygdala, dorsomedial prefrontal cortex (dmPFC), and ventromedial PFC, supporting both bottom-up affective processes for ambiguity representation/perception and top-down cognitive processes for ambiguity resolution/decision. Direct recordings from the human neurosurgical patients showed that the responses of amygdala and dmPFC neurons were modulated by the level of emotion ambiguity, and amygdala neurons responded earlier than dmPFC neurons, reflecting the bottom-up process for ambiguity processing. We further found parietal-frontal coherence and delta-alpha cross-frequency coupling involved in encoding emotion ambiguity. We replicated the EEG coherence result using independent experiments and further showed modulation of the coherence. EEG source connectivity revealed that the dmPFC top-down regulated the activities in other brain regions. Lastly, we showed altered behavioral responses in neuropsychiatric patients who may have dysfunctions in amygdala-PFC functional connectivity. Together, using multimodal experimental and analytical approaches, we have delineated a neural network that underlies processing of emotion ambiguity. Significance Statement: A large number of different brain regions participate in emotion processing. However, it remains elusive how these brain regions interact and coordinate with each other and collectively encode emotions, especially when the task requires orchestration between different brain areas. In this study, we employed multimodal approaches that well complemented each other to comprehensively study the neural mechanisms of emotion ambiguity. Our results provided a systematic understanding of the amygdala-PFC network underlying emotion ambiguity with fMRI-based connectivity, EEG coordination of cortical regions, synchronization of brain rhythms, directed information flow of the source signals, and latency of single-neuron responses. Our results further shed light on neuropsychiatric patients who have abnormal amygdala-PFC connectivity.