Theta oscillations between the ventromedial prefrontal cortex and amygdala support dynamic representations of threat and safety

The amygdala exhibits distinct different activity patterns to threat and safety stimuli. Animal studies have demonstrated that the fear (i.e., threat) and extinction (i.e., safety) memory are encoded by the amygdala and its interaction with the ventromedial prefrontal cortex (vmPFC). Recent studies in both animals and humans suggest that the inter-regional interaction between amygdala and vmPFC can be supported by theta oscillations during fear processing. However, the mechanism by which the human vmPFC-amygdala pathway dynamically supports neural representations of the same stimulus remains elusive, as it alternatively reflects threat and safety situations. To investigate this phenomenon, we conducted intracranial EEG recordings in drug-resistant epilepsy patients (n = 8) with implanted depth electrodes who performed a fear conditioning and extinction task. This task was designed with a fixed structure whereby specific CS+ stimulus could be either safe (never paired with US) or threatening (possibly paired with US) based on an implicit rule during fear acquisition. Our findings showed that the stimulus embodying potential threat information was accompanied by increased theta activities in amygdala during both fear acquisition and early extinction. Furthermore, the learning of safety information was associated with enhanced theta-related direction from the vmPFC to the amygdala. This study provided directly electrophysiological evidence supporting the dynamic oscillatory modulation of threat and safety representations in the human amygdala-vmPFC circuit, and suggests that amygdala safety processing depends on theta inputs from the vmPFC in both fear acquisition and extinction.