Looking beyond Fear and Extinction Learning: Considering Novel Treatment Targets for Anxiety (2024)

Extinction

Given these extinction deficits, numerous attempts have aimed to enhance extinction learning using a variety of pharmacological agents [see review, 18]; however, few studies have detected direct effects on extinction learning. A recent study found that, relative to placebo controls, two-week administration of escitalopram to healthy adults prior to fear conditioning facilitated faster extinction [19]. New evidence also suggests that D-cylcoserine (DCS) given prior to exposure therapy accelerates the efficiency, not efficacy or durability, of treatment response in social anxiety disorder patients [20].While trying to enhance extinction learning seems to be a sensible approach to reduce anxiety, fear and extinction learning activate a cascade of cognitive processes that extend beyond learning itself. Targeting fear generalization, memory consolidation, and reconsolidation may yield novel avenues for addressing inappropriate fear responses and anxiety

Fear Generalization

Following fear learning, fear may broaden or generalize to stimuli sharing similar characteristics. For example, if someone is bitten by a particular dog, fear may generalize to other dogs. In fear generalization paradigms in a research setting, the CS+ and CS− may be two different sized rings, and the generalization stimuli may be morphed images varying in size between the CS+ and CS− [21]. As shown in Figure 1-A, fear generalization is expressed as a quadratic pattern of fear response, with higher fear to stimuli most similar to the CS+ and fear levels decreasing as similarity declines [21]. Generalization effects of learned fear have been reported using both self-report and psychophysiological measures [22, 21]. Initial evidence using these indices suggests fear generalization is stable over 8 months [23]; therefore, treatment manipulations targeting generalization can be attributed to the intervention rather than changes over time.

More recently, the neural underpinnings of fear generalization have received attention. Several brain regions are sensitive to subtle differences in threat and safety using fear generalization paradigms. In neuroimaging studies in healthy adults, insula responses showed generalization gradients with maximal response to the CS+, suggesting sensitivities to threat. The vmPFC, on the other hand, has shown the opposite pattern with highest response to the CS− [24, 25], suggesting sensitivities to safety. In Lissek et al. 2013, the hippocampus is also implicated in discriminating safety, with an activation pattern similar to the vmPFC. Additionally, hippocampal-vmPFC functional connectivity increased with greater dissimilarity to the CS+ [25].

Anxious adults have exhibited evidence of overgeneralization (i.e., fear generalizes to more stimuli) compared to healthy controls. Adults with panic disorder and generalized anxiety disorder (GAD) showed reduced quadratic patterns of subjective and startle response along the stimulus continuum than healthy controls[26, 27], indicating more fear generalization. Consistent with these behavioral and psychophysiological indices, women with GAD also showed a less steep gradient in vmPFC activation than healthy controls, which predicted diagnostic status [28, 29]. Additionally, less vmPFC cortical thickness and greater functional vmPFC connectivity with the amgydala and parahippocampal gyrus also predict lower levels of vmPFC threat-safety discrimination [29]. Together, adults with anxiety disorders, relative to healthy adults, may have a lower threshold to detect CS+ features, or alternatively, deficient recruitment of vmPFC to inhibit fear responses.

Stimulus complexity may also influence fear generalization. Some CS stimuli used in fear conditioning paradigms are simple (e.g., colored squares, sized rings) [13, 21], while other studies use complex stimuli (e.g., different women) [30, 22]. Particular stimulus properties may acquire threat-value and the CS- may dictate such features [31]. For example, in Figure 1–1, size differentiates threat (e.g., large ring) and safety (e.g., small ring) rather than any other feature (e.g., color). Evidence suggests that extinguishing the most salient feature of a complex stimulus first may be optimal in preventing fear at retrieval [32]. However, even though separate features of the CS+ may be extinguished through generalization stimuli, fear returns when these features are presented simultaneously [31], suggesting that the CS+ may be viewed holistically. Future studies should investigate how best to extinguish generalizable features to maximize fear reduction.

Complexity of fear learning also extends to the environmental cues associated with fear (i.e., context). Relative to extinguishing a single context, extinguishing multiple contexts attenuates renewal and reinstatement effects [33–35]. However, it is unclear whether the reduced fear after extinguishing multiple contexts is due to increased generalization of extinction or additional knowledge gained by alternating contexts. Regardless, treatments conducted in the clinic must be generalized to personal surroundings; therefore, understanding the complexity associated with different contexts is necessary for successful treatment.

Consolidation

Through consolidation, the different UCS associations learned during fear acquisition (Figure 1-B) and extinction (Figure 1-C) are converted into long-term memories. Rapid eye movement (REM) sleep is involved in emotional memory consolidation [36] and activates the fear-related neural circuitry, including the amygdala and hippocampus [37]. Sleep may enhance and refine negative memories by strengthening connectivity between fear circuit structures such as the amygdala, hippocampus, and vmPFC during memory retrieval [38]. As such, REM sleep plays an important role in the consolidation of both fear learning as well as extinction learning.

Acute sleep deprivation following fear acquisition affects the later expression of learned fear. In animal studies, depriving REM sleep following fear learning impairs consolidation of fear memories, as indexed by lower levels of behavioral freezing to a previously feared tone [39]. Additionally, longer amounts of sleep deprivation produce larger associated impairments in fear memory consolidation in rats [40]. Although replication is needed, more recent work with a translational focus has shown that acute sleep deprivation impairs fear memory consolidation in humans. For example, less REM sleep following fear acquisition resulted in lower shock expectancy ratings, smaller skin conductance responses, and less basolateral amygdala activation to the conditioned stimulus [41]. This result suggests weaker consolidation of learned fear, consistent with animal studies [42].

Although acute sleep deprivation following fear learning may result in reduced fear expression, chronic sleep deprivation in humans may lead to increased threat sensitivity. Chronically disrupting sleep results in greater amygdala activation to threatening stimuli, possibly resulting from decreased ventral ACC inhibition of the amygdala [43]. Therefore, acute sleep deprivation may lower short-term fear responses, at the expense of higher long-term fear responses, producing a maladaptive cycle that leads to the development and maintenance of fear-related disorders such as post-traumatic stress disorder (PTSD) [44]

Similar to its role in fear learning, sleep also plays a key role in consolidating extinction learning. The consolidation of extinction learning can be enhanced by increasing the amount of sleep following extinction learning. For example, participants who slept for longer intervals following extinction learning, compared to a sleep deprivation group, demonstrated higher levels of extinction retention [45]. Consolidation of extinction learning can also be enhanced by reducing the time interval between extinction learning and sleep. For instance, if extinction learning is closely followed by sleep, fear reductions generalize from an extinguished to a non-extinguished conditioned stimulus [46].

Clinical applications of this work may include increasing sleep following extinction-based treatments (e.g., exposure therapy). Increasing sleep following exposure therapy produces larger reductions in anxiety symptoms. One study demonstrated that afternoon naps as short as 1.5 hours immediately following successful exposure therapy for spider phobia resulted in significantly lower reported levels of distress and catastrophic cognitions at one-week follow-up [47]. Additionally, more restful sleep following CBT sessions for social anxiety disorder was associated with larger symptom reductions at subsequent sessions [48]. Mirroring findings in basic extinction learning paradigms [46], reducing the time interval between exposure therapy and sleep also enhances treatment outcomes. For example, sleep more closely following a single session of exposure therapy produced greater reductions in physiological reactivity to a feared stimulus, which also generalized to new stimuli [49]. In short, sleep may reduce both threat- related cognitions and physiological reactivity to feared stimuli, as well as increase the rate, retention and generalization of these fear reductions [49].

Despite these promising findings, however, the mechanisms that produce enhanced consolidation of extinction learning require elucidation. Several explanations for the effects of sleep on extinction learning have been proposed using sleep deprivation studies. First, neural data suggest that sleep deprivation may impair the new CS+ association (i.e., the CS+ no longer predicts the UCS). Compared to a control group, participants who were sleep deprived following extinction learning demonstrated more left middle temporal gyrus activation in response to a CS+ during an extinction retention task [45], possibly reflecting greater UCS expectancy violation [50]. Alternatively, sleep deprivation may impair learning that the context does not predict the UCS. In other words, rather than impairing the consolidation of amygdala-dependent cued memory, sleep deprivation may impair the consolidation of hippocampus-dependent contextual memory [51, 52]

In summary, modifying sleep patterns may serve as a tool to reduce fear. However, the mechanisms for the implementation of sleep modifications should be considered. Reducing sleep following fear learning impairs the consolidation of fear memories. However, utilizing this approach in anxiety disorders may have long-term contraindications as a more chronic course of sleep deprivation increases threat sensitivity and may impair extinction learning. In contrast, improving consolidation by either increasing the amount or proximity of sleep following extinction learning has demonstrated more clinical utility. This approach has already demonstrated direct clinical relevance given that sleep has been shown to augment exposure therapy in a number of ways. As previously noted, however, further research that examines a longer time course of these processes is required to understand the stability of these processes over time and to guide the development of interventions targeting these processes.

In addition to manipulating sleep, fear and extinction memory consolidation may be targeted in other ways. For example, transcranial direct stimulation of the dorsolateral prefrontal cortex (dlPFC) following fear acquisition reduces subsequent fear responses measured during extinction learning, which suggests that neural stimulation of this region disrupts fear memory consolidation [53]. This stimulation may also alter connectivity between structures involved in the fear circuit. For example, resting-state connectivity between the amygdala and dlPFC increases following conditioning and is correlated with explicit memory of the CS+-UCS association learned during fear acquisition [54].

Pharmacological interventions may also be employed to target the consolidation of extinction memories. Although some pharmacological interventions are administered prior to extinction learning, group differences are often delayed, suggesting that the consolidation of the extinction memory may underlie the pharmacological changes, rather than extinction per se. For example, intranasal oxytocin administered to healthy adults prior to extinction learning improved extinction retention [55]. Similarly, fear reduction after reinstatement was enhanced in a sample of healthy adults who were given either DCS or valproic acid prior to extinction [56]. Relative to placebo controls, cannabinoids, namely synthetic Delta-9-tetrahydrocannabinol (THC), given prior to extinction learning enhanced extinction retention and elicited greater ventromedial PFC and hippocampus activation in healthy adults [57, 58]. Additional evidence suggests that cannabinoids, i.e., synthetic cannabidiol, given after extinction enhances consolidation of extinction learning relative to placebo [59].

Other studies conducted in clinical contexts may provide additional support that enhancing consolidation following extinction is clinically viable. Relative to placebo controls, administering cortisol before psychotherapy sessions improves symptom reduction in individuals with specific phobia [60, 61], though one study found symptom reduction only at long-term follow-up [61]. Additionally, some research suggests that DCS enhances extinction learning, although more recent evidence indicates that symptom reduction with DCS augmentation was dependent on low fear levels following exposure sessions (i.e., successful exposure therapy) [62, 63]. In contrast, symptoms worsen when DCS is administered prior to treatment sessions that do not lower fear levels (i.e., unsuccessful exposure therapy) [62]. Similarly, although yombinine, a noradrenergic antagonist, enhances self-reported reductions of social anxiety following exposure therapy, the effects were moderated by session success [64]. Therefore, DCS and yombinine may target consolidation mechanisms indiscriminately. Future research should examine the viability of utilizing neural-stimulation and pharmacological interventions to enhance consolidation of extinction memory specifically in the context of extinction-based learning treatments such as exposure therapy.

Reconsolidation

When a consolidated memory is recalled it becomes temporarily unstable, rendering it vulnerable to disruption. Updates to the memory that occur during this period of instability are referred to as reconsolidation [65]. While reconsolidation is not a new field of research, it has recently regained interest [see review, see 66], likely due to its potential for clinical utility in the treatment of anxiety disorders.

Reconsolidation studies follow a general format. First, participants are conditioned to fear two or more stimuli. The next day, one of the conditioned stimuli is presented without an unconditioned stimulus pairing (e.g., electrical shock, loud noise) to reactivate the fear memory, rendering it unstable. Once the fear memory is labile, pharmacological or behavioral manipulations can disrupt this memory during the reconsolidation window (e.g., within 6+ hours post activation). In behavioral studies that condition two CS+, the unreminded CS+ serves as a within-subject control measure. A successful reconsolidation update effect would show a fear reduction in skin-conductance, startle response, or subjective ratings during subsequent retrieval [66]. See Figure 1-D.

Human reconsolidation studies often administer propranolol, a beta-adrenergic receptor blocker that mimics the effects of protein synthesis inhibitors used in animal studies [67, 68]. Propranolol paradigms have had relative success in reducing fear following reconsolidation in non-clinical samples [69, 70], though some findings are limited to self-reported fear reductions [71]. Instructed paradigms may be a more clinically-relevant approach to reduce fear because the CS+-UCS contingencies are based on explicit cognitions, rather than implicit classical conditioning. Using an instructed fear paradigm, participants receiving propranolol prior to extinction learning experienced successful reduction in both the behavioral expression of fear (as measured by startle eye blink) and subjective feelings of anxiety, while the placebo group exhibited return of the fear memory [72]. This study suggests that a reconsolidation paradigm can alter cognitively-based fear memories. Some question the success of propranolol to influence older memories [73]; however, propranolol reduced physiological reactivity following reactivation of past traumatic events relative to placebo control [74]. Additionally, compared to controls, significant symptom improvement was detected after individuals with PTSD activated long-term traumatic memories using script-driven imagery and received deep transcranial magnetic stimulation of the mPFC [75].

Like pharmacological manipulations, behavioral manipulations presented within the reconsolidation window can also interfere with reactivated memories. Studies employing these paradigms are largely variants of Schiller et al., 2010 [76], which showed that conducting extinction training within the reconsolidation window effectively reduced skin conductance responses to conditioned stimuli during retention. Some studies have replicated these findings using a different UCS [e.g., a loud, aversive noise; 77] and different reinforcement schedules [78]; however, others have failed to see reductions in fear expression when conducting extinction during the reconsolidation window [79, 80]. The reason these studies fail to observe fear reduction is unclear. The use of fear-relevant stimuli [e.g., fearful faces; 80] may explain some of the discrepancy, though, previous studies using fear-relevant stimuli in a propranolol paradigm have successfully reduced fear following extinction during the reconsolidation window [69, 70].

Two recent studies have investigated neural correlates of fear reduction following extinction training during the reconsolidation window conducted[78, 81]. Individuals that underwent extinction training during the reconsolidation window recruited the vmPFC and amygdala-vmPFC coupling less in response to the reminded CS+ during re-extinction than standard extinction procedures conducted [78, 81]. This finding is clinically relevant as extinction training during reconsolidation may recruit regions related to fear (i.e., amygdala) less.

Taken together, reconsolidation research is moving in a promising direction towards clinical applications. For instance, behavioral paradigms may target fear memory processes more directly than pharmacological approaches. Yet, researchers need to improve ecological validity by using fear-relevant stimuli, imagined stimuli, or different UCSs. Upcoming study designs should also continue to test the durability of using reconsolidation update mechanisms in clinical applications. For example, some researchers have demonstrated continued effects in healthy samples at one-month [70] and one-year follow up [76], but further research is needed in clinical samples, including pediatric age ranges, and individuals at-risk for clinical anxiety.

Development and Puberty

The cognitive processes such as those described above may play a role in the etiology and maintenance of anxiety. Adolescence may be a key developmental stage when these perturbations emerge. Adolescence is a transitional period that confers risk for development of multiple anxiety disorders including social anxiety disorder and GAD [82]. Targeting interventions during this period when these processes are most malleable may prove beneficial.

Adolescence is a period of both physical and psychological changes. Across development, the brain shows evidence of increased synaptic pruning and myelination [83]. In adolescence, an imbalance between cortical and subcortical regions activation may lead to heightened emotional responses [84]. As such, several reviews have highlighted the need to study fear conditioning and extinction across development [85–88].

As in adults, differential fear conditioning has been demonstrated in children and adolescents [89]. Some studies indicate older children show more discrimination compared to young children. In addition, fear generalization patterns appear more analogous to adults than younger children [90]. Consistent with animal work investigating the effects of development [91], healthy adolescents may exhibit deficits in extinction. For example, healthy adolescents reported more fear to the CS+ relative to the CS− after extinction [92, 30], suggesting extinction resistance. In addition, adolescents had deficient extinction learning compared to adults and younger children [87]. Although youth have deficits in extinction, to our knowledge, only one study on youth with obsessive-compulsive disorder has attempted to enhance extinction learning using DCS [93].

Identifying youth at-risk for chronic anxiety in adulthood during these vulnerable periods may alter the course of anxiety disorders [94]. Consistent with prior work in at-risk youth [95], 7–14 year old children with maternal history of an anxiety disorder exhibited impaired extinction compared to low-risk youth, as evidenced by greater physiological reactivity to CS+ than CS-. In addition, SCR to both CS increased with continued extinction training, rather than decreasing [96]. Longitudinal studies that examine extended time courses are needed to identify developmental trajectories in both at-risk and clinical populations.

Recent neuroimaging studies have detected developmental differences during conditioning [97] and extinction retention [89]. During fear acquisition, healthy adolescents, compared to healthy adults, showed less self-reported discrimination and greater amygdala activation in response to the CS+ relative to the CS− [97]. Consistent with previous work in anxious adults [98], both adults and adolescents with anxiety disorders exhibited subgenual ACC hypoactivation during extinction retention relative to healthy groups, highlighting regions that are anxiety-related, independent of development. Anxious youth showed different perturbations in vmPFC activation than anxious adults [89], highlighting regions that are anxiety-related and developmentally sensitive. Together, these findings suggest that adolescence may be a prime target for interventions that disrupt fear memories and/or enhance extinction-related processes.

Puberty may also impact fear and safety learning. For instance, physiological reactivity is increased in puberty [e.g.,99]; however, few studies have investigated the effects pubertal status on fear and safety learning in adolescence. Puberty is also accompanied by hormonal changes and the onset of menstrual cycle. Studies in adult women suggest that estrogen impacts fear extinction, with endogenous and exogenous estradiol modulating vmPFC activation and enhancing extinction retention [100, 101]. Future studies in development should investigate the impact of puberty and hormonal changes during and following fear conditioning.

Conflict of Interest

Jennifer Britton is an Assistant Professor at the University of Miami. Britton has received grants from the NIMH, the University of Miami and NARSAD. Britton received the You Choose Award to sponsor neuroimaging workshop from the University of Miami, College of Arts and Sciences and SEEDS. Travis Evans and Michael Hernandez declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the authors.

Papers of particular interest or published recently, have been highlighted with a *.

1. Milad MR, Quirk GJ. Fear extinction as a model for translational neuroscience: ten years of progress. Annual review of psychology. 2012;63:129–151. [PMC free article] [PubMed] [Google Scholar]This review discusses recent advances in fear extinction studies conducted in animals and humans.

2. Vervliet B, Craske MG, Hermans D. Fear extinction and relapse: state of the art. Annual review of clinical psychology. 2013;9:215–248. [PubMed] [Google Scholar]This review highlights reasons why fear returns and how certain approaches may enhance durability of extinction.

3. Bouton ME, Westbrook RF, Corcoran KA, Maren S. Contextual and temporal modulation of extinction: behavioral and biological mechanisms. Biological psychiatry. 2006;60(4):352–360. [PubMed] [Google Scholar]

4. Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology. 2008;33(1):56–72. [PMC free article] [PubMed] [Google Scholar]

5. LeDoux JE. Emotion circuits in the brain. Annual review of neuroscience. 2000;23:155–184. [PubMed] [Google Scholar]

6. Delgado MR, Olsson A, Phelps EA. Extending animal models of fear conditioning to humans. Biol Psychol. 2006;73(1):39–48. [PubMed] [Google Scholar]

7. LaBar KS, Gatenby JC, Gore JC, LeDoux JE, Phelps EA. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron. 1998;20(5):937–945. [PubMed] [Google Scholar]

8. O'Reilly RC, Rudy JW. Computational principles of learning in the neocortex and hippocampus. Hippocampus. 2000;10(4):389–397. [PubMed] [Google Scholar]

9. Kalisch R, Korenfeld E, Stephan KE, Weiskopf N, Seymour B, Dolan RJ. Context-dependent human extinction memory is mediated by a ventromedial prefrontal and hippocampal network. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006;26(37):9503–9511. [PMC free article] [PubMed] [Google Scholar]

10. Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biological psychiatry. 2007;62(5):446–454. [PubMed] [Google Scholar]

11. Bechara A, Tranel D, Damasio H, Adolphs R, Rockland C, Damasio AR. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science. 1995;269(5227):1115–1118. [PubMed] [Google Scholar]

12. Milad MR, Quirk GJ, Pitman RK, Orr SP, Fischl B, Rauch SL. A role for the human dorsal anterior cingulate cortex in fear expression. Biological psychiatry. 2007;62(10):1191–1194. [PubMed] [Google Scholar]

13. Phelps EA, Delgado MR, Nearing KI, LeDoux JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron. 2004;43(6):897–905. [PubMed] [Google Scholar]

14. Lissek S, Powers AS, McClure EB, Phelps EA, Woldehawariat G, Grillon C, et al. Classical fear conditioning in the anxiety disorders: a meta-analysis. Behaviour research and therapy. 2005;43(11):1391–1424. [PubMed] [Google Scholar]

15. Gazendam FJ, Kindt M. Worrying affects associative fear learning: a startle fear conditioning study. PLoS One. 2012;7(4):e34882. [PMC free article] [PubMed] [Google Scholar]

16. Grupe DW, Nitschke JB. Uncertainty is associated with biased expectancies and heightened responses to aversion. Emotion. 2011;11(2):413–424. [PMC free article] [PubMed] [Google Scholar]

17. Grillon C, Charney DR. In the face of fear: anxiety sensitizes defensive responses to fearful faces. Psychophysiology. 2011;48(12):1745–1752. [PMC free article] [PubMed] [Google Scholar]

18. Fitzgerald PJ, Seemann JR, Maren S. Can fear extinction be enhanced? A review of pharmacological and behavioral findings. Brain research bulletin. 2013 [PMC free article] [PubMed] [Google Scholar]This review discusses different pharamacological treatments (e.g., amino acid receptor, monoamine, cholinergic, cannabioniod, peptide, and steroid hormone modulators) and behavioral approaches (e.g., massed extinction, multiple context, and reconsolidtion update mechanisms) used in animals and humans to enhance extinction.

19. Bui E, Orr SP, Jacoby RJ, Keshaviah A, LeBlanc NJ, Milad MR, et al. Two weeks of pretreatment with escitalopram facilitates extinction learning in healthy individuals. Human psychopharmacology. 2013;28(5):447–456. [PubMed] [Google Scholar]

20. Hofmann SG, Smits JA, Rosenfield D, Simon N, Otto MW, Meuret AE, et al. D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. The American journal of psychiatry. 2013;170(7):751–758. [PMC free article] [PubMed] [Google Scholar]

21. Lissek S, Biggs AL, Rabin SJ, Cornwell BR, Alvarez RP, Pine DS, et al. Generalization of conditioned fear-potentiated startle in humans: experimental validation and clinical relevance. Behaviour research and therapy. 2008;46(5):678–687. [PMC free article] [PubMed] [Google Scholar]

22. Haddad AD, Xu M, Raeder S, Lau JY. Measuring the role of conditioning and stimulus generalisation in common fears and worries. Cognition & emotion. 2013;27(5):914–922. [PubMed] [Google Scholar]

23. Torrents-Rodas D, Fullana MA, Bonillo A, Andion O, Molinuevo B, Caseras X, et al. Testing the temporal stability of individual differences in the acquisition and generalization of fear. Psychophysiology. 2014 [PubMed] [Google Scholar]The stability of fear learning and fear generalization is crucial for the development of effective and targeted treatments. This manuscript is one of the first to examine stability of both acquisition and fear generalization using repeated and different stimulus sets.

24. Greenberg T, Carlson JM, Cha J, Hajcak G, Mujica-Parodi LR. Neural reactivity tracks fear generalization gradients. Biol Psychol. 2013;92(1):2–8. [PubMed] [Google Scholar]

25. Lissek S, Bradford DE, Alvarez RP, Burton P, Espensen-Sturges T, Reynolds RC, et al. Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study. Social cognitive and affective neuroscience. 2013 [PMC free article] [PubMed] [Google Scholar]This study replicates findings reported by Greenberg et al., 2013, showing increasing sensitivity to threat in the insula and increasing sensitivity to safety in ventromedial prefrontal cortex (vmPFC). This article finds an additional relationship in the hippocampus that complements the vmPFC finding.

26. Lissek S, Rabin S, Heller RE, Lukenbaugh D, Geraci M, Pine DS, et al. Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. The American journal of psychiatry. 2010;167(1):47–55. [PMC free article] [PubMed] [Google Scholar]

27. Lissek S, Kaczkurkin AN, Rabin S, Geraci M, Pine DS, Grillon C. Generalized Anxiety Disorder Is Associated with Overgeneralization of Classically Conditioned Fear. Biological psychiatry. 2013 [PMC free article] [PubMed] [Google Scholar]

28. Greenberg T, Carlson JM, Cha J, Hajcak G, Mujica-Parodi LR. Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization. Depress Anxiety. 2013;30(3):242–250. [PubMed] [Google Scholar]This paper reports anxiety-related differences in the neural correlates of fear generalization. Women with generalized anxiety disorder exhibit less vmPFC activation across the continuum of generalization stimuli compared to healthy controls.

29. Cha J, Greenberg T, Carlson JM, Dedora DJ, Hajcak G, Mujica-Parodi LR. Circuit-wide structural and functional measures predict ventromedial prefrontal cortex fear generalization: implications for generalized anxiety disorder. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2014;34(11):4043–4053. [PMC free article] [PubMed] [Google Scholar]

30. Lau JY, Lissek S, Nelson EE, Lee Y, Roberson-Nay R, Poeth K, et al. Fear conditioning in adolescents with anxiety disorders: results from a novel experimental paradigm. Journal of the American Academy of Child and Adolescent psychiatry. 2008;47(1):94–102. [PMC free article] [PubMed] [Google Scholar]

31. Vervliet B, Geens M. Fear generalization in humans: Impact of feature learning on conditioning and extinction. Neurobiology of learning and memory. 2013 [PubMed] [Google Scholar]

32. Jones CE, Ringuet S, Monfils MH. Learned together, extinguished apart: reducing fear to complex stimuli. Learning & memory. 2013;20(12):674–685. [PMC free article] [PubMed] [Google Scholar]

33. Balooch SB, Neumann DL, Boschen MJ. Extinction treatment in multiple contexts attenuates ABC renewal in humans. Behaviour research and therapy. 2012;50(10):604–609. [PubMed] [Google Scholar]

34. Laborda MA, Miller RR. Preventing return of fear in an animal model of anxiety: additive effects of massive extinction and extinction in multiple contexts. Behavior therapy. 2013;44(2):249–261. [PMC free article] [PubMed] [Google Scholar]

35. Dunsmoor JE, Hs F, Zielinski DJ, Labar KS. Extinction in multiple virtual reality contexts diminishes fear reinstatement in humans. Neurobiology of learning and memory. 2014 [PMC free article] [PubMed] [Google Scholar]

36. Walker MP, van der Helm E. Overnight therapy? The role of sleep in emotional brain processing. Psychological bulletin. 2009;135(5):731–748. [PMC free article] [PubMed] [Google Scholar]

37. Perogamvros L, Dang-Vu TT, Desseilles M, Schwartz S. Sleep and dreaming are for important matters. Frontiers in psychology. 2013;4:474. [PMC free article] [PubMed] [Google Scholar]

38. Payne JD, Kensinger EA. Sleep Leads to Changes in the Emotional Memory Trace: Evidence from fMRI. Journal of Cognitive Neuroscience. 2011;23(6):1285–1297. [PubMed] [Google Scholar]

39. Kumar T, Jha SK. Sleep deprivation impairs consolidation of cued fear memory in rats. PLoS ONE. 2012;7(10) [PMC free article] [PubMed] [Google Scholar]

40. Hagewoud R, Whitcomb SN, Heeringa AN, Havekes R, Koolhaas JM, Meerlo P. A time for learning and a time for sleep: The effect of sleep deprivation on contextual fear conditioning at different times of the day. Sleep: Journal of Sleep and Sleep Disorders Research. 2010;33(10):1315–1322. [PMC free article] [PubMed] [Google Scholar]

41. Menz MM, Rihm JS, Salari N, Born J, Kalisch R, Pape HC, et al. The role of sleep and sleep deprivation in consolidating fear memories. NeuroImage. 2013;75:87–96. [PubMed] [Google Scholar]Deprivation of REM sleep impaired the subjective, physiological, and neural expression of fear when participants were re-exposed to the conditioned stimuli in a subsequent session two days later.

42. Popa D, Duvarci S, Popescu AT, Lena C, Pare D. Coherent amygdalocortical theta promotes fear memory consolidation during paradoxical sleep. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(14):6516–6519. [PMC free article] [PubMed] [Google Scholar]

43. Motomura Y, Kitamura S, Oba K, Terasawa Y, Enomoto M, Katayose Y, et al. Sleep debt elicits negative emotional reaction through diminished amygdala-anterior cingulate functional connectivity. PLoS One. 2013;8(2):e56578. [PMC free article] [PubMed] [Google Scholar]

44. van Liempt S. Sleep disturbances and PTSD: a perpetual circle? European journal of psychotraumatology. 2012:3. [PMC free article] [PubMed] [Google Scholar]

45. Spoormaker VI, Schroter MS, Andrade KC, Dresler M, Kiem SA, Goya-Maldonado R, et al. Effects of rapid eye movement sleep deprivation on fear extinction recall and prediction error signaling. Human brain mapping. 2012;33(10):2362–2376. [PMC free article] [PubMed] [Google Scholar]

46. Pace-Schott EF, Milad MR, Orr SP, Rauch SL, Stickgold R, Pitman RK. Sleep promotes generalization of extinction of conditioned fear. Sleep: Journal of Sleep and Sleep Disorders Research. 2009;32(1):19–26. [PMC free article] [PubMed] [Google Scholar]

47. Kleim B, Wilhelm FH, Temp L, Margraf J, Wiederhold BK, Rasch B. Sleep enhances exposure therapy. Psychological medicine. 2013:1–9. [PubMed] [Google Scholar]

48. Zalta AK, Dowd S, Rosenfield D, Smits JA, Otto MW, Simon NM, et al. Sleep quality predicts treatment outcome in CBT for social anxiety disorder. Depress Anxiety. 2013;30(11):1114–1120. [PMC free article] [PubMed] [Google Scholar]

49. Pace-Schott EF, Verga PW, Bennett TS, Spencer RM. Sleep promotes consolidation and generalization of extinction learning in simulated exposure therapy for spider fear. Journal of psychiatric research. 2012;46(8):1036–1044. [PMC free article] [PubMed] [Google Scholar]This study suggests that sleep following exposure therapy facilitates retention and generalization of extinction learning. Compared to a morning exposure group, adults with spider phobia who slept following exposure therapy (evening exposure) demonstrated greater reductions in both subjective and physiological measures of fear when exposed to new spider stimuli.

50. Spoormaker VI, Andrade KC, Schroter MS, Sturm A, Goya-Maldonado R, Samann PG, et al. The neural correlates of negative prediction error signaling in human fear conditioning. NeuroImage. 2011;54(3):2250–2256. [PubMed] [Google Scholar]

51. Graves LA, Heller EA, Pack AI, Abel T. Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning. Learning & memory. 2003;10(3):168–176. [PMC free article] [PubMed] [Google Scholar]

52. Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, et al. Sleep deprivation impairs cAMP signalling in the hippocampus. Nature. 2009;461(7267):1122–1125. [PMC free article] [PubMed] [Google Scholar]

53. Asthana M, Nueckel K, Muhlberger A, Neueder D, Polak T, Domschke K, et al. Effects of transcranial direct current stimulation on consolidation of fear memory. Frontiers in psychiatry. 2013;4:107. [PMC free article] [PubMed] [Google Scholar]

54. Schultz DH, Balderston NL, Helmstetter FJ. Resting-state connectivity of the amygdala is altered following Pavlovian fear conditioning. Frontiers in human neuroscience. 2012;6:242. [PMC free article] [PubMed] [Google Scholar]Demonstrates that the connectivity within the fear circuitry is strengthened following classical conditioning.

55. Acheson D, Feifel D, de Wilde S, Mckinney R, Lohr J, Risbrough V. The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. Psychopharmacology. 2013;229(1):199–208. [PMC free article] [PubMed] [Google Scholar]

56. Kuriyama K, Honma M, Soshi T, Fujii T, Kim Y. Effect of D-cycloserine and valproic acid on the extinction of reinstated fear-conditioned responses and habituation of fear conditioning in healthy humans: a randomized controlled trial. Psychopharmacology (Berl) 2011;218(3):589–597. [PubMed] [Google Scholar]

57. Rabinak CA, Angstadt M, Lyons M, Mori S, Milad MR, Liberzon I, et al. Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans. Neurobiology of learning and memory. 2013;113:125–134. [PMC free article] [PubMed] [Google Scholar]Individuals receiving cannabinoid prior to extinction exhibited greater ventromedial prefrontal cortex and hippocampus activation during extinction recall.

58. Rabinak CA, Angstadt M, Sripada CS, Abelson JL, Liberzon I, Milad MR, et al. Cannabinoid facilitation of fear extinction memory recall in humans. Neuropharmacology. 2013;64:396–402. [PMC free article] [PubMed] [Google Scholar]

59. Das RK, Kamboj SK, Ramadas M, Yogan K, Gupta V, Redman E, et al. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology. 2013;226(4):781–792. [PubMed] [Google Scholar]

60. de Quervain DJ, Bentz D, Michael T, Bolt OC, Wiederhold BK, Margraf J, et al. Glucocorticoids enhance extinction-based psychotherapy. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(16):6621–6625. [PMC free article] [PubMed] [Google Scholar]

61. Soravia LM, Heinrichs M, Winzeler L, Fisler M, Schmitt W, Horn H, et al. Glucocorticoids Enhance in Vivo Exposure-Based Therapy of Spider Phobia. Depress Anxiety. 2013 [PubMed] [Google Scholar]

62. Smits JA, Rosenfield D, Otto MW, Marques L, Davis ML, Meuret AE, et al. D-cycloserine enhancement of exposure therapy for social anxiety disorder depends on the success of exposure sessions. Journal of psychiatric research. 2013;47(10):1455–1461. [PMC free article] [PubMed] [Google Scholar]

63. Smits JA, Rosenfield D, Otto MW, Powers MB, Hofmann SG, Telch MJ, et al. D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia. Biological psychiatry. 2013;73(11):1054–1058. [PMC free article] [PubMed] [Google Scholar]

64. Smits JA, Rosenfield D, Davis ML, Julian K, Handelsman PR, Otto MW, et al. Yohimbine Enhancement of Exposure Therapy for Social Anxiety Disorder: A Randomized Controlled Trial. Biological psychiatry. 2013 [PubMed] [Google Scholar]

65. Walker MP, Brakefield T, Hobson JA, Stickgold R. Dissociable stages of human memory consolidation and reconsolidation. Nature. 2003;425(6958):616–620. [PubMed] [Google Scholar]

66. Schiller D, Phelps EA. Does reconsolidation occur in humans? Frontiers in behavioral neuroscience. 2011;5:24. [PMC free article] [PubMed] [Google Scholar]

67. Gelinas JN, Nguyen PV. Beta-adrenergic receptor activation facilitates induction of a protein synthesis-dependent late phase of long-term potentiation. The Journal Of Neuroscience: The Official Journal Of The Society For Neuroscience. 2005;25(13):3294–3303. [PMC free article] [PubMed] [Google Scholar]

68. Judge ME, Quartermain D. Characteristics of retrograde amnesia following reactivation of memory in mice. Physiology & Behavior. 1982;28(4):585–590. [PubMed] [Google Scholar]

69. Kindt M, Soeter M, Vervliet B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nature neuroscience. 2009;12(3):256–258. [PubMed] [Google Scholar]

70. Soeter M, Kindt M. Dissociating response systems: erasing fear from memory. Neurobiology of learning and memory. 2010;94(1):30–41. [PubMed] [Google Scholar]

71. Bos MG, Beckers T, Kindt M. The effects of noradrenergic blockade on extinction in humans. Biol Psychol. 2012;89(3):598–605. [PubMed] [Google Scholar]

72. Soeter M, Kindt M. Erasing fear for an imagined threat event. Psychoneuroendocrinology. 2012;37(11):1769–1779. [PubMed] [Google Scholar]Replicates propranolol reconsolidation paradigm using purely cognitive-based, explicitly learned fear/threat associations. This study contrasts studies relying on fear associations formed through behavioral/conditioning principles.

73. Milekic MH, Alberini CM. Temporally graded requirement for protein synthesis following memory reactivation. Neuron. 2002;36(3):521–525. [PubMed] [Google Scholar]

74. Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. Journal of psychiatric research. 2008;42(6):503–506. [PubMed] [Google Scholar]

75. Isserles M, Shalev AY, Roth Y, Peri T, Kutz I, Zlotnick E, et al. Effectiveness of deep transcranial magnetic stimulation combined with a brief exposure procedure in post-traumatic stress disorder--a pilot study. Brain Stimul. 2013;6(3):377–383. [PubMed] [Google Scholar]

76. Schiller D, Monfils MH, Raio CM, Johnson DC, Ledoux JE, Phelps EA. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature. 2010;463(7277):49–53. [PMC free article] [PubMed] [Google Scholar]

77. Oyarzún JP, Lopez-Barroso D, Fuentemilla L, Cucurell D, Pedraza C, Rodriguez-Fornells A, et al. Updating fearful memories with extinction training during reconsolidation: a human study using auditory aversive stimuli. PloS one. 2012;7(6):e38849. [PMC free article] [PubMed] [Google Scholar]Replicates Schiller et al., 2010 using an aversive auditory stimuli as the unconditioned stimulus. Similar to previous work, fear is reduced at extinction retention when extinction is conducted during relative to outside the reconsolidation window.

78. Agren T, Engman J, Frick A, Björkstrand J, Larsson E-M, Furmark T, et al. Disruption of reconsolidation erases a fear memory trace in the human amygdala. Science. 2012;337(6101):1550–1552. [PubMed] [Google Scholar]

79. Golkar A, Bellander M, Olsson A, Öhman A. Are fear memories erasable?–reconsolidation of learned fear with fear-relevant and fear-irrelevant stimuli. Frontiers in behavioral neuroscience. 2012:6. [PMC free article] [PubMed] [Google Scholar]

80. Kindt M, Soeter M. Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism. Biological psychology. 2013;92(1):43–50. [PubMed] [Google Scholar]

81. Schiller D, Kanen JW, LeDoux JE, Monfils MH, Phelps EA. Extinction during reconsolidation of threat memory diminishes prefrontal cortex involvement. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(50):20040–20045. [PMC free article] [PubMed] [Google Scholar]Provides neural data as evidence that behavioral reconsolidation update mechanisms operate by recruiting the PFC circuitry less, demonstrating the inhibition of learned fear responses.

82. Beesdo K, Pine DS, Lieb R, Wittchen HU. Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder. Archives of general psychiatry. 2010;67(1):47–57. [PubMed] [Google Scholar]

83. Giedd JN. Structural magnetic resonance imaging of the adolescent brain. Annals of the New York Academy of Sciences. 2004;1021:77–85. [PubMed] [Google Scholar]

84. Casey BJ, Ruberry EJ, Libby V, Glatt CE, Hare T, Soliman F, et al. Transitional and translational studies of risk for anxiety. Depress Anxiety. 2011;28(1):18–28. [PMC free article] [PubMed] [Google Scholar]

85. Baker KD, Den ML, Graham BM, Richardson R. A window of vulnerability: Impaired fear extinction in adolescence. Neurobiology of learning and memory. 2013 [PubMed] [Google Scholar]

86. Jovanovic T, Nylocks KM, Gamwell KL, Smith A, Davis TA, Norrholm SD, et al. Development of fear acquisition and extinction in children: Effects of age and anxiety. Neurobiology of learning and memory. 2013 [PMC free article] [PubMed] [Google Scholar]

87. Pattwell SS, Duhoux S, Hartley CA, Johnson DC, Jing D, Elliott MD, et al. Altered fear learning across development in both mouse and human. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(40):16318–16323. [PMC free article] [PubMed] [Google Scholar]This review highlights differences in extinction between younger children, adolescents and adults in both animal and humans.

88. Shechner T, Hong M, Britton JC, Pine DS, Fox NA. Fear conditioning and extinction across development: Evidence from human studies and animal models Biological psychology. in press [PMC free article] [PubMed] [Google Scholar]

89. Britton JC, Grillon C, Lissek S, Norcross MA, Szuhany KL, Chen G, et al. Response to learned threat: An FMRI study in adolescent and adult anxiety. The American journal of psychiatry. 2013;170(10):1195–1204. [PMC free article] [PubMed] [Google Scholar]This study is the first to examine the effects of anxiety and age on psychophysiological indices of fear conditioning and extinction and neural correlates of extinction recall in the same study. Comparisons among these four groups during threat appraisal allows anxiety-related perturbations independent of age (i.e., subgenual anterior cingulate hypoactivation) and developmentally-sensitive perturbations relevant to anxiety (i.e., ventromedial prefrontal cortex activation patterns) to be discovered.

90. Glenn CR, Klein DN, Lissek S, Britton JC, Pine DS, Hajcak G. The development of fear learning and generalization in 8–13 year-olds. Developmental psychobiology. 2012;54(7):675–684. [PMC free article] [PubMed] [Google Scholar]

91. Kim JH, Richardson R. New findings on extinction of conditioned fear early in development: theoretical and clinical implications. Biological psychiatry. 2010;67(4):297–303. [PubMed] [Google Scholar]

92. Haddad AD, Lissek S, Pine DS, Lau JY. How do social fears in adolescence develop? Fear conditioning shapes attention orienting to social threat cues. Cognition & emotion. 2011;25(6):1139–1147. [PMC free article] [PubMed] [Google Scholar]

93. Storch EA, Murphy TK, Goodman WK, Geffken GR, Lewin AB, Henin A, et al. A preliminary study of D-cycloserine augmentation of cognitive-behavioral therapy in pediatric obsessive-compulsive disorder. Biological psychiatry. 2010;68(11):1073–1076. [PMC free article] [PubMed] [Google Scholar]

94. Chocyk A, Przyborowska A, Makuch W, Majcher-Maslanka I, Dudys D, Wedzony K. The effects of early-life adversity on fear memories in adolescent rats and their persistence into adulthood. Behavioural brain research. 2014;264:161–172. [PubMed] [Google Scholar]

95. Craske MG, Waters AM, Lindsey Bergman R, Naliboff B, Lipp OV, Negoro H, et al. Is aversive learning a marker of risk for anxiety disorders in children? Behaviour research and therapy. 2008;46(8):954–967. [PMC free article] [PubMed] [Google Scholar]

96. Waters AM, Peters RM, Forrest KE, Zimmer-Gembeck M. Fear acquisition and extinction in offspring of mothers with anxiety and depressive disorders. Developmental cognitive neuroscience. 2014;7:30–42. [PMC free article] [PubMed] [Google Scholar]Replicates Craske et al., 2008. Children at-risk of developing anxiety disorders showed resistance to extinction.

97. Lau JY, Britton JC, Nelson EE, Angold A, Ernst M, Goldwin M, et al. Distinct neural signatures of threat learning in adolescents and adults. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(11):4500–4505. [PMC free article] [PubMed] [Google Scholar]

98. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biological psychiatry. 2009;66(12):1075–1082. [PMC free article] [PubMed] [Google Scholar]

99. Schmitz A, Grillon C, Avenevoli S, Cui L, Merikangas KR. Developmental investigation of fear-potentiated startle across puberty. Biol Psychol. 2014;97:15–21. [PMC free article] [PubMed] [Google Scholar]

100. Zeidan MA, Igoe SA, Linnman C, Vitalo A, Levine JB, Klibanski A, et al. Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biological psychiatry. 2011;70(10):920–927. [PMC free article] [PubMed] [Google Scholar]

101. Milad MR, Goldstein JM, Orr SP, Wedig MM, Klibanski A, Pitman RK, et al. Fear conditioning and extinction: influence of sex and menstrual cycle in healthy humans. Behavioral neuroscience. 2006;120(6):1196–1203. [PubMed] [Google Scholar]