Abstract:

Fear memories formed in traumatic experience is pathological basis of stress-related disorders. New memories initially persist in a fragile state and are susceptible to being disrupted by behavioral or pharmacological treatments. Exposure therapy based on extinction is a common treatment for pathological fear. However, extinction training that occurs shortly after fear conditioning is less effective than delayed extinction training in yielding long-term extinction memory, a phenomenon that is known as immediate extinction deficit (IED). The IED may be linked to levels of stress and emotional arousal at the onset of extinction training and event segmentation. If the stress and emotional arousal levels are high at the outset of extinction training, the outcomes of immediate extinction are not influenced by context change or event boundary between fear conditioning and extinction (i.e. event segmentation), but rather mainly affected by the high stress state that can impair the consolidation of extinction memory, resulting in IED. When the levels of stress and emotional arousal are moderate before the onset of extinction training, there is no difference between immediate extinction and delayed extinction, and both of them couldn’t prevent fear relapse. When the stress and emotional arousal levels are low at the time of extinction intervention, the early extinction was more effective than delayed extinction intervention, which could disrupt the consolidation of fear memory and prevent the return of fear. In addition, under moderate or low stress levels, the effect of immediate extinction would be also susceptible to event segmentation. That is, if there is a clear event boundary between fear acquisition and extinction, the event boundary may guide selective consolidation to prioritize the consolidation of emotional information in memory (fear memory) -- at the expense of related but conflicting information (extinction memory) experienced shortly thereafter, leading to IED; if without this event boundary, immediate extinction may retroactively interfere with the consolidation of fear memories and prevent the deficit; but the evidence for this is not yet sufficient. In addition, results from human fear conditioning suggest that the IED phenomenon is not inevitable, even though the electric shock was calibrated to be at the same level deemed “highly annoying but not painful” by each participant. Explanations for this may be that people's criterion for the feeling “highly annoying but not painful” has varied greatly, resulting in the actual stress and emotional arousal level of each participant is different, that is, not all participant are in a high arousal state, therefore IED phenomenon is unstable.
The infralimbic (IL) that is a subdivision of the medial prefrontal cortex (mPFC) plays a key role in the consolidation and retrieval of extinction memory. The basolateral amygdala (BLA) and mPFC form strong reciprocal synaptic connections that play a key role in acquisition and extinction of fear memories. Fear extinction depends on the activities in these two projection pathways, BLA-IL and IL-BLA, which are trade-off. The neurobiological mechanisms of IED may involve that: (1) stress-induced activation of the locus coeruleus norepinephrine (LC-NE) system evokes extensive release of NE in BLA through LC-projecting neurons, leading to hyperactivity of BLA; and (2) stress-activated corticotropin releasing factor (CRF) system in BLA triggers the release of CRF that binds G-protein-coupled receptors (CRFR1), resulting in hyperexcitability of BLA; then overactive BLA inputs suppress the activity of IL via feedforward inhibition of projection neurons, which further impair the consolidation of extinction memories, causing IED. Future studies should examine whether the IED is just an aberration or early extinction acts as a secondary trauma which can continually damage the ability to extinguish fear memory, instead, contributes to the development of stress-related disorders, and explore how to optimize the clinical application of immediate extinction. 

Key words: fear conditioning, immediate extinction, stress level, event segmentation