Daniela Schiller

Preventing the return of fear in humans using reconsolidation update mechanisms

Recent research on changing fears has examined targeting reconsolidation. During reconsolidation, stored information is rendered labile after being retrieved. Pharmacological manipulations at this stage result in an inability to retrieve the memories at later times, suggesting that they are erased or persistently inhibited. Unfortunately, the use of these pharmacological manipulations in humans can be problematic. Here we introduce a non-invasive technique to target the reconsolidation of fear memories in humans. We provide evidence that old fear memories can be updated with non-fearful information provided during the reconsolidation window. As a consequence, fear responses are no longer expressed, an effect that lasted at least a year and was selective only to reactivated memories without affecting others. These findings demonstrate the adaptive role of reconsolidation as a window of opportunity to rewrite emotional memories, and suggest a non-invasive technique that can be used safely in humans to prevent the return of fear.

From Fear to Safety and Back: Reversal of Fear in the Human Brain

Fear learning is a rapid and persistent process that promotes defense against threats and reduces the need to relearn about danger. However, it is also important to flexibly readjust fear behavior when circumstances change. Indeed, a failure to adjust to changing conditions may contribute to anxiety disorders. A central, yet neglected aspect of fear modulation is the ability to flexibly shift fear responses from one stimulus to another if a once-threatening stimulus becomes safe or a once-safe stimulus becomes threatening. In these situations, the inhibition of fear and the development of fear reactions co-occur but are directed at different targets, requiring accurate responding under continuous stress. To date, research on fear modulation has focused mainly on the shift from fear to safety by using paradigms such as extinction, resulting in a reduction of fear. The aim of the present study was to track the dynamic shifts from fear to safety and from safety to fear when these transitions occur simultaneously. We used functional neuroimaging in conjunction with a fear-conditioning reversal paradigm. Our results reveal a unique dissociation within the ventromedial prefrontal cortex between a safe stimulus that previously predicted danger and a “naive” safe stimulus. We show that amygdala and striatal responses tracked the fear-predictive stimuli, flexibly flipping their responses from one predictive stimulus to another. Moreover, prediction errors associated with reversal learning correlated with striatal activation. These results elucidate how fear is readjusted to appropriately track environmental changes, and the brain mechanisms underlying the flexible control of fear.

The role of the striatum in aversive learning and aversive prediction errors

Neuroeconomic studies of decision making have emphasized reward learning as critical in the representation of value-driven choice behaviour. However, it is readily apparent that punishment and aversive learning are also significant factors in motivating decisions and actions. In this paper, we review the role of the striatum and amygdala in affective learning and the coding of aversive prediction errors (PEs). We present neuroimaging results showing aversive PE-related signals in the striatum in fear conditioning paradigms with both primary (shock) and secondary (monetary loss) reinforcers. These results and others point to the general role for the striatum in coding PEs across a broad range of learning paradigms and reinforcer types.

Overlapping neural systems mediating extinction, reversal and regulation of fear

Learned fear is a process allowing quick detection of associations between cues in the environment and prediction of imminent threat. Adaptive function in a changing environment, however, requires organisms to quickly update this learning and have the ability to hinder fear responses when predictions are no longer correct. Here we focus on three strategies that can modify conditioned fear, namely extinction, reversal and regulation of fear, and review their underlying neural mechanisms. By directly comparing neuroimaging data from three separate studies that employ each strategy, we highlight overlapping brain structures that comprise a general circuitry in the human brain. This circuitry potentially enables the flexible control of fear, regardless of the particular task demands.

Differential roles of human striatum and amygdala in associative learning

Although the human amygdala and striatum have both been implicated in associative learning, only the striatums contribution has been consistently computationally characterized. Using a reversal learning task, we found that amygdala blood oxygen level–dependent activity tracked associability as estimated by a computational model, and dissociated it from the striatal representation of reinforcement prediction error. These results extend the computational learning approach from striatum to amygdala, demonstrating their complementary roles in aversive learning.

Erasing Fear Memories with Extinction Training

Decades of behavioral studies have confirmed that extinction does not erase classically conditioned fear memories. For this reason, research efforts have focused on the mechanisms underlying the development of extinction-induced inhibition within fear circuits. However, recent studies in rodents have uncovered mechanisms that stabilize and destabilize fear memories, opening the possibility that extinction might be used to erase fear memories. This symposium focuses on several of these new developments, which involve the timing of extinction training. Extinction-induced erasure of fear occurs in very young rats, but is lost with the development of perineuronal nets in the amygdala that render fear memories impervious to extinction. Moreover, extinction administered during the reconsolidation phase, when fear memory is destabilized, updates the fear association as safe, thereby preventing the return of fear, in both rats and humans. The use of modified extinction protocols to eliminate fear memories complements existing pharmacological strategies for strengthening extinction.

A neural mechanism of first impressions

Evaluating social others requires processing complex information. Nevertheless, we can rapidly form an opinion of an individual during an initial encounter. Moreover, people can vary in these opinions, even though the same information is provided. We investigated the brain mechanisms that give rise to the impressions that are formed on meeting a new person. Neuroimaging revealed that responses in the amygdala and the posterior cingulate cortex (PCC) were stronger while encoding social information that was consistent, relative to inconsistent, with subsequent evaluations. In addition, these responses scaled parametrically with the strength of evaluations. These findings provide evidence for encoding differences on the basis of subsequent evaluations, suggesting that the amygdala and PCC are important for forming first impressions.

Does Reconsolidation Occur in Humans

Evidence for reconsolidation in non-human animals has accumulated rapidly in the last decade, providing compelling` demonstration for this phenomenon across species and memory paradigms. In vast contrast, scant evidence exists for human reconsolidation to date. A major reason for this discrepancy is the invasive nature of current techniques used to investigate reconsolidation, which are difficult to apply in humans. Pharmacological blockade of reconsolidation, for example, has been typically used in animals as a proof of concept. However, most compounds used in these studies are toxic for humans, and those compounds that are safe target related, but not direct mechanisms of reconsolidation. Thus, although human reconsolidation has been hypothesized, there is limited evidence it actually exists. The best evidence for human reconsolidation emerges from non-invasive techniques that “update” memory during reconsolidation rather than block it, a technique only rarely used in animal research. Here we discuss the current state of human reconsolidation and the challenges ahead. We review findings on reconsolidation of emotional associative, episodic, and procedural memories, using invasive and non-invasive techniques. We discuss the possible interpretation of these results, attempt to reconcile some inconsistencies, and suggest a conceptual framework for future research.

Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement

Significance An advantage of targeting reconsolidation to control reactions to learned threats is that the memory appears to be persistently altered, not inhibited. When these memories are diminished through extinction, the amygdala’s representation remains largely intact and the prefrontal cortex inhibits its expression, thus allowing the learned responses to recover. Targeting reconsolidation, therefore, should eliminate the necessity of prefrontal inhibition. We tested this hypothesis by contrasting standard extinction with extinction occurring during reconsolidation. We observed that behavioral interference of reconsolidation appears to bypass the prefrontal circuitry of extinction, inducing a more persistent loss of learned responses. Application of this strategy, which targets underlying learned threat processes, to fear and anxiety disorders may provide a more effective approach to treatment. Controlling learned defensive responses through extinction does not alter the threat memory itself, but rather regulates its expression via inhibitory influence of the prefrontal cortex (PFC) over amygdala. Individual differences in amygdala–PFC circuitry function have been linked to trait anxiety and posttraumatic stress disorder. This finding suggests that exposure-based techniques may actually be least effective in those who suffer from anxiety disorders. A theoretical advantage of techniques influencing reconsolidation of threat memories is that the threat representation is altered, potentially diminishing reliance on this PFC circuitry, resulting in a more persistent reduction of defensive reactions. We hypothesized that timing extinction to coincide with threat memory reconsolidation would prevent the return of defensive reactions and diminish PFC involvement. Two conditioned stimuli (CS) were paired with shock and the third was not. A day later, one stimulus (reminded CS+) but not the other (nonreminded CS+) was presented 10 min before extinction to reactivate the threat memory, followed by extinction training for all CSs. The recovery of the threat memory was tested 24 h later. Extinction of the nonreminded CS+ (i.e., standard extinction) engaged the PFC, as previously shown, but extinction of the reminded CS+ (i.e., extinction during reconsolidation) did not. Moreover, only the nonreminded CS+ memory recovered on day 3. These results suggest that extinction during reconsolidation prevents the return of defensive reactions and diminishes PFC involvement. Reducing the necessity of the PFC–amygdala circuitry to control defensive reactions may help overcome a primary obstacle in the long-term efficacy of current treatments for anxiety disorders.

Evidence for Recovery of Fear Following Immediate Extinction in Rats and Humans.

Fear responses can be eliminated through extinction, a procedure involving the presentation of fear-eliciting stimuli without aversive outcomes. Extinction is believed to be mediated by new inhibitory learning that acts to suppress fear expression without erasing the original memory trace. This hypothesis is supported mainly by behavioral data demonstrating that fear can recover following extinction. However, a recent report by Myers and coworkers suggests that extinction conducted immediately after fear learning may erase or prevent the consolidation of the fear memory trace. Since extinction is a major component of nearly all behavioral therapies for human fear disorders, this finding supports the notion that therapeutic intervention beginning very soon after a traumatic event will be more efficacious. Given the importance of this issue, and the controversy regarding immediate versus delayed therapeutic interventions, we examined two fear recovery phenomena in both rats and humans: spontaneous recovery (SR) and reinstatement. We found evidence for SR and reinstatement in both rats and humans even when extinction was conducted immediately after fear learning. Thus, our data do not support the hypothesis that immediate extinction erases the original memory trace, nor do they suggest that a close temporal proximity of therapeutic intervention to the traumatic event might be advantageous.