Pattern analysis of neuroimaging data reveals novel insights on threat learning and extinction in humans.

Several decades of rodent neurobiology research have identified a network of brain regions that support Pavlovian threat conditioning and extinction, focused predominately on the amygdala, hippocampus, and medial prefrontal cortex (mPFC). Surprisingly, functional magnetic resonance imaging (fMRI) studies have shown inconsistent evidence for these regions while humans undergo threat conditioning and extinction. In this review, we suggest that translational neuroimaging efforts have been hindered by reliance on traditional univariate analysis of fMRI. Whereas univariate analyses average activity across voxels in a given region, multivariate pattern analyses (MVPA) leverage the information present in spatial patterns of activity. MVPA therefore provides a more sensitive analysis tool to translate rodent neurobiology to human neuroimaging. We review human fMRI studies using MVPA that successfully bridge rodent models of amygdala, hippocampus, and mPFC function during Pavlovian learning. We also highlight clinical applications of these information-sensitive multivariate analyses. In sum, we advocate that the field should consider adopting a variety of multivariate approaches to help bridge cutting-edge research on the neuroscience of threat and anxiety.

Rewarded Extinction Increases Amygdalar Connectivity and Stabilizes Long-Term Memory Traces in the vmPFC.

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala and the ventral striatum, whereas the retrieval of standard-extinction memories was associated with connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC). One month later, the retrieval of both standard-extinction and rewarded-extinction was associated with amygdala-vmPFC connectivity. However, only rewarded extinction created a stable memory trace in the vmPFC, identified through overlapping multivariate patterns of fMRI activity from extinction to 24-h and one-month retrieval. These findings provide new evidence that reward may generate a more stable and enduring memory trace of attenuated threat in humans.SIGNIFICANCE STATEMENT Prevalent treatments for pathologic fear and anxiety are based on the principles of Pavlovian extinction. Unfortunately, extinction forms weak memories that only temporarily inhibit the retrieval of threat associations. Thus, to increase the translational relevance of extinction research, it is critical to investigate whether extinction can be augmented to form a more enduring memory, especially after long intervals. Here, we used a multiday fMRI paradigm in humans to compare the short-term and long-term neurobehavioral effects of aversive-to-appetitive counterconditioning (CC), a form of augmented extinction. Our results provide novel evidence that including an appetitive stimulus during extinction can reduce short-term threat relapse and stabilize the memory trace of extinction in the ventromedial prefrontal cortex (vmPFC), for at least one month after learning.

Neural reinstatement reveals divided organization of fear and extinction memories in the human brain.

Neurobiological research in rodents has revealed that competing experiences of fear and extinction are stored as distinct memory traces in the brain. This divided organization is adaptive for mitigating overgeneralization of fear to related stimuli that are learned to be safe while also maintaining threat associations for unsafe stimuli. The mechanisms involved in organizing these competing memories in the human brain remain unclear. Here, we used a hybrid form of Pavlovian conditioning with an episodic memory component to identify overlapping multivariate patterns of fMRI activity associated with the formation and retrieval of fear versus extinction. In healthy adults, distinct regions of the medial prefrontal cortex (PFC) and hippocampus showed selective reactivation of fear versus extinction memories based on the temporal context in which these memories were encoded. This dissociation was absent in participants with posttraumatic stress disorder (PTSD) symptoms. The divided neural organization of fear and extinction may support flexible retrieval of context-appropriate emotional memories, while their disorganization may promote overgeneralization and increased fear relapse in affective disorders.

Emotional learning retroactively enhances item memory but distorts source attribution.

An adaptive memory system should prioritize information surrounding a powerful learning event that may prove useful for predicting future meaningful events. The behavioral tagging hypothesis provides a mechanistic framework to interpret how weak experiences persist as durable memories through temporal association with a strong experience. Memories are composed of multiple elements, and different mnemonic aspects of the same experience may be uniquely affected by mechanisms that retroactively modulate a weakly encoded memory. Here, we investigated how emotional learning affects item and source memory for related events encoded close in time. Participants encoded trial-unique category exemplars before, during, and after Pavlovian fear conditioning. Selective retroactive enhancements in 24-h item memory were accompanied by a bias to misattribute items to the temporal context of fear conditioning. The strength of this source memory bias correlated with participants' retroactive item memory enhancement, and source misattribution to the emotional context predicted whether items were remembered overall. In the framework of behavioral tagging: Memory attribution was biased to the temporal context of the stronger event that provided the putative source of memory stabilization for the weaker event. We additionally found that fear conditioning selectively and retroactively enhanced stimulus typicality ratings for related items, and that stimulus typicality also predicted overall item memory. Collectively, these results provide new evidence that items related to emotional learning are misattributed to the temporal context of the emotional event and judged to be more representative of their semantic category. Both processes may facilitate memory retrieval for related events encoded close in time.

Thought suppression inhibits the generalization of fear extinction.

A challenge for translating fear extinction research into clinical treatments for stress and anxiety disorders is that extinction learning tends not to generalize beyond the treatment context. This may be because the hippocampus limits the expression of extinction memories. Consequently, downregulating the hippocampus may help to promote the generalization of extinction learning. One nonpharmacological strategy to downregulate hippocampal activity in humans is motivated forgetting, in which a participant deliberately attempts to suppress the encoding and/or retrieval of episodic memories. Here, we evaluated whether this strategy could facilitate extinction generalization by augmenting extinction training with thought suppression. Participants were threat conditioned using two conditioned stimulus (CS) categories paired with an electrical shock. Subsequently, during extinction training, one CS category was accompanied by thought suppression. Participants were tested for extinction generalization 24h later with conceptual variations of the extinguished stimuli. Contrary to our prediction, we found that extinction training paired with thought suppression resulted in enhanced shock expectancy (i.e., worse generalization) relative to standard extinction. We conclude that thought suppression during memory encoding likely acts as an inhibitory cue that blocks the acquisition of extinction memories, and therefore may not be a viable tactic to promote extinction generalization in the treatment of anxiety disorders.

Generalization of conditioned fear along a dimension of increasing positive valence.

The amount of fear evoked by potential threats is oftentimes proportional to the overlap in shared features with known threats. An adaptive learning system should therefore extract relevant features from threat stimuli to successfully detect other novel threats in the environment. But what if the most relevant feature of a threat stimulus is emotionally positive? Here, we used Pavlovian fear conditioning to ask whether people extract positive emotional features of a fear conditioned stimulus (CS) to selectively generalize to other stimuli that contain positive features. In a between subjects design, we first paired a picture of a face expressing either a slight amount of happiness or fear with an electrical shock to the wrist. We then tested fear generalization to modified face stimuli of the same identity expressing more or less happiness or fear. Both groups exhibited biased physiological arousal (a peak shift) to a face stimulus with the most exaggerated emotional expression, regardless of valence. Fear generalization diminished to unreinforced happy faces over the course of testing, whereas arousal was maintained to unreinforced fearful faces throughout testing. Finally, subjects fear conditioned to a slightly happy face were accurate at retrospectively identifying the correct CS, whereas subjects fear conditioned to a fearful face retrospectively misidentified a more fearful face as the threat CS. These findings suggest that positive emotional features extracted from a known threat can guide biased fear generalization, but that generalization is maintained by a dimension of increasing fear which also produces retrospective biases in threat intensity estimation.

Contextual reinstatement promotes extinction generalization in healthy adults but not PTSD.

For episodic memories, reinstating the mental context of a past experience improves retrieval of memories formed during that experience. Does context reinstatement serve a similar role for implicit, associative memories such as fear and extinction? Here, we used a fear extinction paradigm to investigate whether the retrieval of extinction (safety) memories is associated with reactivation of the mental context from extinction memory formation. In a two-day Pavlovian conditioning, extinction, and renewal protocol, we collected functional MRI data while healthy adults and adults with PTSD symptoms learned that conditioned stimuli (CSs) signaled threat through association with an electrical shock. Following acquisition, conceptually related exemplars from the CS category no longer signaled threat (i.e., extinction). Critically, during extinction only, task-irrelevant stimuli were presented between each CS trial to serve as "context tags" for subsequent identification of the possible reinstatement of this extinction context during a test of fear renewal the next day. We found that healthy adults exhibited extinction context reinstatement, as measured via multivariate pattern analysis of fMRI data, in the medial temporal lobe that related to behavioral performance, such that greater reinstatement predicted CSs being rated as safe instead of threatening. Moreover, context reinstatement positively correlated with univariate activity in the ventromedial prefrontal cortex and hippocampus, regions which are thought to be important for extinction learning. These relationships were not observed in the PTSD symptom group. These findings provide new evidence of a contextual reinstatement mechanism that helps resolve competition between the retrieval of opposing associative memories of threat and safety in the healthy adult brain that is dysregulated in PTSD.

Behavioral and neural processes in counterconditioning: Past and future directions.

Counterconditioning refers both to the technique and putative process by which behavior is modified through a new association with a stimulus of an opposite valence. Similar to extinction, counterconditioning is considered a form of inhibition that interferes with the expression of the originally learned response without erasing it. But whereas interest in extinction continues to rise, counterconditioning has received far less attention. Here, we provide an in-depth review of counterconditioning research and detail whether counterconditioning is any more effective than extinction at preventing relapse of the originally learned behavior. We consider the clinical implications of counterconditioning, describe recent neurobiological and neuroimaging research in this area, and consider future avenues in need of further investigation.