Neuroscience of fear extinction: Implications for assessment and treatment of fear-based and anxiety related disorders

Behaviour Research and Therapy xxx (2014) 1e7

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Neuroscience of fear extinction: Implications for assessment and treatment of fear-based and anxiety related disorders Mohammed R. Milad a, *, Blake L. Rosenbaum a, Naomi M. Simon b a

Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, 149 13th St., Charlestown, MA 02129, USA Center for Anxiety and Traumatic Stress Disorders, Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, 1 Bowdoin Square, 6th Floor, Boston, MA 02114, USA

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 15 May 2014 Received in revised form 14 August 2014 Accepted 14 August 2014 Available online xxx

Current exposure-based therapies aimed to reduce pathological fear and anxiety are now amongst the most effective interventions for trauma and anxiety related disorders. Nevertheless, they can be further improved to enhance initial and long-term outcomes. It is now widely accepted that a greater understanding of the neurobiological mechanisms of fear extinction is needed to further develop and identify novel effective targeted treatments as well as prevention strategies for fear-based and anxiety-related disorders. Guided by elegant mechanistic, cellular, and molecular preclinical reports, data from imaging studies are beginning to shape our understanding of how fear is quelled in the human brain. In this article, we briefly review the neural circuits underlying fear extinction in rodents and healthy humans. We then review how these circuits may fail to extinguish fear in patients with anxiety disorders. We end with a discussion examining how fear extinction research may lead to significant advances of current therapeutics for anxiety disorders. © 2014 Elsevier Ltd. All rights reserved.

Keywords: Fear conditioning vmPFC Amygdala Exposure therapy Yohimbine DCS

Why fear extinction? From the viewpoint of basic neuroscience, understanding how our brains learn to fear and how not to fear is an intriguing question. While such a fascination may have been the impetus for the initial wave of preclinical studies conducted in this domain, the rapid advancement of neuroimaging tools and their implementation in studying the psychopathology of anxiety disorders has generated a new translational research approach that merges basic neuroscience and clinical data. This merger has been a work-inprogress over the past decade and thus far has been helpful in advancing our understanding of how fear memories are formed and maintained in the human brain, as well as how such fear memories may be inappropriately expressed and contribute to underlying psychopathology in patients with anxiety disorders. Pavlovian fear conditioning is one such experimental paradigm that allows for a translational and reverse-translational approach. In this paradigm, subjects learn to form associations between simple cues, such as a black square presented along with a mild

* Corresponding author. Tel.: þ1 617 724 8533. E-mail address: [email protected] (M.R. Milad).

electric shock delivered to the fingers of the subject. Subsequent presentations of the black square paired with the more aversive shock can elicit a number of conditioned responses including changes in heart rate and elevation in skin conductance responding. This phase of the experiment is referred to as the fear acquisition phase, as the subject begins to associate the biologically relevant shock with the originally benign square. Repeated presentations of the now conditioned black square (conditioned CS, CSþ) without any unconditioned stimuli (US, the electric shock) lead to the gradual diminution, or extinction, of the conditioned response. This is referred to as within-session extinction learning. The memory of this extinction learning can be assessed after a delay (often 24 h later) in a phase referred to as the extinction retention test (between-session extinction). The expression of this extinction memory can be manipulated and gated by varying the context in which fear extinction is first learned and subsequently tested. The context dependent nature of extinction is critical to modulating the expression or inhibition of fear responses. This model of Pavlovian fear conditioning presents several advantages to study the psychopathology of anxiety disorders. A key feature of some anxiety disorders, and posttraumatic stress disorder (PTSD) in particular, is a failure to appropriately inhibit, or extinguish, fear (Hermans, Craske, Mineka, & Lovibond, 2006; Milad, Rauch, Pitman, & Quirk, 2006; Pitman, Shin, & Rauch,

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Please cite this article in press as: Milad, M. R., et al., Neuroscience of fear extinction: Implications for assessment and treatment of fear-based and anxiety related disorders, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.08.006

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2001). Individuals with PTSD or phobic anxiety disorders, such as panic disorder (PD), agoraphobia and social anxiety disorder (SAD), avoid fear-provoking situations and stimuli, or endure them by employing a range of different “safety behaviors” that are designed to protect the individual from harm or negative feared outcomes (Lovibond, Saunders, Weidemann, & Mitchell, 2008). Avoidance and the use of safety behaviors, therefore, prevent patients from challenging unrealistic beliefs and so prevent fear extinction (Lovibond, Mitchell, Minard, Brady, & Menzies, 2009). Hence, the fear extinction model provides a direct measure of what is widely accepted to be a central underlying dysfunction across phobic anxiety disorders and PTSD. Moreover, exposure therapy is based on and parallels an extinction procedure used in animal studies of fear inhibition. In addition to potentially detecting the neural basis for the underlying dysfunction in anxiety disorders, extinction paradigms can also be used as a valid model of the most effective psychological treatment for anxiety disorders and PTSD. Data examining potential differences in fear extinction processes across the anxiety disorders are lacking, and potential areas of overlap and differences between the different disorders have yet to be fully researched. For example, whereas generalized anxiety disorders (GAD) are principally characterized by worry and a generalized nervousness rather than cue-based phobic anxiety, PD with agoraphobia is more clearly a fear-based disorder (Breier, Charney, & Heninger, 1986). It remains unknown if differences in the neurobiology of fear extinction processes are universally present or may underlie such differences in phenomenology across all the anxiety disorders. Comparisons of animal studies with human neuroimaging studies suggest considerable similarity between the neural structures involved in extinction in the rodent and in the human, highlighting another advantage of the fear extinction model (Delgado, Nearing, Ledoux, & Phelps, 2008). The cross-species validity of the extinction model permits the use of rodents to address questions that are not initially feasible to study in human subjects, while maintaining confidence that such findings can ultimately be translated to the affected human population. For example, animal studies allow researchers to test the effects of novel drugs on extinction and subsequent relapse, as well as the associated neurobiological effects of such drugs on underlying fear neurocircuitry. Neural circuits mediating fear acquisition and its extinction The neurobiology of fear acquisition is well characterized in rodents and humans (Maren & Quirk, 2004). Briefly, it is widely accepted that the basolateral complex of the amygdala is the main neural structure in which information about the conditioned and unconditioned stimuli converge (Ledoux, 2000). There is also evidence from rodent studies that the prelimbic division of the medial prefrontal cortex is involved in regulating the expression of learned fear (Burgos-Robles, Vidal-Gonzalez, & Quirk, 2009; Burgos-Robles, Vidal-Gonzalez, Santini, & Quirk, 2007; Corcoran & Quirk, 2007). In addition, it has been shown that the central amygdala is a key component in the circuitry devoted to fear acquisition and expression (Duvarci & Pare, 2014). The centromedial subdivision receives inhibitory inputs from other subnuclei of the amygdala including the lateral central amygdala subdivision that gate the expression of fear (Haubensak et al., 2010). Activation of this lateral subdivision of the amygdala is required for fear acquisition, while the basolateral amygdala along with the inhibitory interneurons (intercalated cells) are involved in the acquisition of fear extinction (Ciocchi et al., 2010). Using functional magnetic resonance imaging (fMRI), it has been shown that humans show robust increases in activity in the

amygdala and dorsal anterior cingulate (which appears to be functionally analogous to the rodent prelimbic cortex) during fear acquisition and expression (Knight, Smith, Cheng, Stein, & Helmstetter, 2004; Linnman, Rougemont-Bucking, Beucke, Zeffiro, & Milad, 2011; Milad, Quirk, et al., 2007; Phelps, Delgado, Nearing, & Ledoux, 2004). Fear extinction, on the other hand, involves interactions between the infralimbic region of the medial prefrontal cortex, the basolateral complex of the amygdala, and the hippocampus (Milad & Quirk, 2012). It is proposed that when an extinguished cue is presented in the extinction training context, the hippocampus activates the infralimbic region, which in turn activates inhibitory interneurons in the basolateral amygdala that inhibit the output neurons in the central amygdala, thus preventing conditioned responding (Herry et al., 2010). In contrast, when the extinguished cue is presented in a context other than the extinction training context, the hippocampus does not activate the infralimbic cortex and central amygdala activity is not inhibited, thus conditioned responding returns (Quirk & Mueller, 2008). Functional MRI has revealed remarkable preservation of this circuitry between rodents and humans (Milad & Quirk, 2012). Specifically, earlier fMRI studies demonstrated that the amygdala exhibits increased activation to the conditioned stimulus during early extinction training, and this activation decreases across extinction training (LaBar, Gatenby, Gore, Ledoux, & Phelps, 1998; Phelps et al., 2004). Subsequent studies have consistently demonstrated that extinction recall (which inhibits conditioned fear responding) is associated with increased activity in the ventromedial prefrontal cortex (vmPFC) (Kalisch et al., 2006; Milad, Wright, et al., 2007; Phelps et al., 2004), a structure that has been proposed to be the human homolog of the rat infralimbic cortex. Furthermore, it has been shown using structural MRI that extinction recall is positively correlated with the thickness of the vmPFC (Hartley, Fischl, & Phelps, 2011; Milad et al., 2005). Several studies have also demonstrated evidence for increased hippocampal activity during extinction recall (Kalisch et al., 2006; Milad, Wright, et al., 2007). Furthermore, one study reported increased hippocampal and vmPFC activity during recall in the extinction context, but not in the original conditioning context (Milad, Wright, et al., 2007), supporting the idea that the hippocampus modulates the expression of the extinction memory depending on contextual information. Such data have clear clinical implications, demonstrating a role for effective hippocampal function and detection of context on effectively controlling fear expression in specific contexts. Collectively, there is much evidence suggesting that a distinct neural circuitry involving interactions between the amygdala, vmPFC, and hippocampus underlies the ability to extinguish fear, and that this circuitry has been preserved across evolution. Is the functional integrity of the fear extinction network impaired across the anxiety disorders? Structural and functional abnormalities of the brain regions mediating fear extinction has been reported across the anxiety disorders using an ample array of tasks. For example, in symptom provocation studies, it has been shown that blood flow in the medial frontal gyrus is reduced in PTSD participants compared to trauma-exposed controls when exposed to trauma reminders, and medial frontal gyrus blood flow was inversely correlated with changes in amygdala blood flow (Shin et al., 2004). Heightened amygdala (Rauch et al., 2000; Shin et al., 2005) and diminished vmPFC activity (Shin et al., 2005) have also been reported in subjects with PTSD while viewing fearful faces during fMRI, compared to trauma-exposed controls. Similar findings have been reported

Please cite this article in press as: Milad, M. R., et al., Neuroscience of fear extinction: Implications for assessment and treatment of fear-based and anxiety related disorders, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.08.006

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for specific phobia. For example, spider phobics exhibited increased amygdala, insula cortex, anterior cingulate, and dorsolateral prefrontal cortex activation when viewing spider-related images compared to neutral images, a finding that was absent in nonphobic controls (Etkin & Wager, 2007; Straube, Mentzel, Glauer, & Miltner, 2004). One recent study (Hermann et al., 2009) examined brain activity using fMRI in spider phobics who were asked to voluntarily up- and down-regulate their emotions elicited by spider imagery, and by non-phobic but generally aversive imagery, using a cognitive reappraisal strategy. Spider phobics exhibited increased dorsal anterior cingulate and insula cortex activity, but reduced vmPFC activity, when attempting to regulate emotional responses to spider imagery, whereas no such changes were observed during regulation toward aversive, phobic-irrelevant imagery. This suggests that the same neural circuitry may regulate both automatic fear-inhibition tasks (i.e., laboratory fear extinction, where no explicit instruction to regulate emotions is given) and effortful fearinhibition tasks (i.e., where an explicit instruction to regulate emotions is given). Furthermore, this suggests that there may be a deficit in this circuitry in people with spider phobia. Similar impairments in the fear extinction network have been observed in patients with PD using the faces paradigm (for example, see Pillay, Gruber, Rogowska, Simpson, & Yurgelun-Todd, 2006). A recent study showed aberrant responses within the vmPFC, ventral striatum and the amygdala during the fear acquisition phase in patients with PD (Tuescher et al., 2011). Moreover, reduced cortical volume in the dACC as well as the rACC has been reported in PD (Asami et al., 2008). Similar impairments in the functional responsiveness of some aspects of this fear network across varying paradigms have also been reported for obsessive compulsive disorder (particularly for the medial and lateral divisions of the PFC) and in GAD (for reviews, see Etkin, Egner, & Kalisch, 2011; Milad & Rauch, 2007). More recent investigations have used imaging techniques to measure structural and functional connectivity between the vmPFC and amygdala and correlate this with anxious traits. Diffusion tensor imaging has shown that the strength of the reciprocal connections between the amygdala and prefrontal cortex predicts trait levels of anxiety, such that a weaker pathway between these brain areas leads to a greater the level of trait anxiety (Kim & Whalen, 2009). A later study reported that amygdala resting state activity was positively coupled to vmPFC activity in low anxious subjects, and negatively coupled to vmPFC activity in high-anxious subjects (Kim, Gee, Loucks, Davis, & Whalen, 2011). Together, these studies suggest that dysfunctions in vmPFC-amygdala connectivity may mediate susceptibility to and/or maintenance of anxiety disorders. In addition to the paradigms mentioned above, the use of loud tone reactivity has been used to examine other physiological responses that are not necessarily associated with an acquired conditioned response across PTSD and OCD. There is a substantial literature demonstrating that increased heart rate (HR) reactivity to loud tones reliably differentiates PTSD from Non-PTSD (Carson et al., 2007). This increased reactivity appears to be acquired with the development of PTSD. Like PTSD, patients with OCD also exhibit exaggerated reactivity to loud tones (Buhlmann et al., 2007). Implementation of this paradigm across the remaining anxiety disorders may provide additional insight to the pathophysiology of anxiety disorders, as this paradigm provides additional measures of the level of reactivity to a simple stimulus, e.g. devoid of a learning component, and may be regarded as an unconditioned stimulus rather than a conditioned one. The continued study of this paradigm will provide the advantage of examining psychophysiological responsiveness to aversive stimuli unrelated to associative learning, which may be important for understanding the psychopathology of disorders like OCD and GAD that are considered to be associated

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with more diffuse nervousness, worry and fear, and do not necessarily align with the classical fear conditioning model. We note, however, that the study of fear extinction and its circuits may not directly inform symptoms other than those related to fear inhibition, such as shame, guilt, and hyperactivity to emotional cues. Nonetheless, we argue that the fear extinction model would still be very useful to understand the psychopathology of fear-based and anxiety disorders, as well as informing the development of novel clinical approaches to treat these disorders. Is fear extinction impaired across the anxiety disorders? Thus far, the vast majority of research efforts have focused on fear extinction in patients with PTSD, while other anxiety disorders remain relatively unstudied. It has been consistently shown that patients with PTSD exhibit an enhanced resistance to extinction (Blechert, Michael, Vriends, Margraf, & Wilhelm, 2007; Jovanovic et al., 2010, 2009; Norrholm et al., 2011; Orr et al., 2000; Peri, Ben Shakhar, Orr, & Shalev, 2000). Similarly, we have reported that individuals with PTSD exhibit deficits in extinction recall, despite the lack of abnormalities in conditioning or within-session extinction, as indexed by enhanced skin conductance responses during recall, but not conditioning or extinction training (Milad et al., 2008; Milad, Pitman, et al., 2009). A PET study demonstrated that in PTSD, fear acquisition is associated with increased resting metabolic activity in the left amygdala, and fear extinction is associated with decreased resting metabolic activity in the vmPFC (Bremner et al., 2005). We extended these results to examine extinction recall the day after extinction training using fMRI. We found that participants with PTSD exhibited reduced activity in the vmPFC and hippocampus, but heightened dACC activity during extinction recall (Milad, Pitman, et al., 2009) (see Fig. 2, from Milad, Pitman, et al., 2009). There was also a positive correlation between the magnitude of extinction recall and both vmPFC and hippocampal activity across all participants. This suggests that hyperactivity within the dACC, and hypoactivity within the vmPFC, may contribute to the impairment in extinction retention observed in PTSD. A subsequent study from our group demonstrated that during extinction recall subjects with PTSD showed both reduced vmPFC activity, and heightened dACC activity in response to the extinction context (Rougemont-Bucking et al., 2011). These findings suggest that hyperactivity within the dACC and hypoactivity within the vmPFC may also mediate an inability to use contextual cues to predict safety, consistent with the persistent and overgeneralized fear of trauma reminders central to the clinical phenomena of PTSD. While PTSD is the most directly parallel clinical condition to the fear conditioning model, requiring a clear trauma or traumas around which the disorder develops, the few available studies that have examined fear conditioning and its extinction in other anxiety disorders consistently demonstrate evidence of impaired fear extinction. For example, individuals with PD exhibit larger skin conductance responses during extinction training and rate the extinguished conditioned stimulus as more unpleasant, despite showing no differences from healthy controls in conditioned responses or valance ratings during or following conditioning (Michael, Blechert, Vriends, Margraf, & Wilhelm, 2007). Enhanced fear learning and activation of the fear network was also recently reported in patients with spider phobia (Schweckendiek et al., 2011). Elevated fear conditioning, with greater conditioned startle to facial expression stimuli, was observed in SAD (Lissek et al., 2008); a previous study reported no differences in fear acquisition but resistance to extinction learning in patients with SAD (Hermann, Ofer, & Flor, 2004). We recently conducted a preliminary study of patients with OCD using a two-day fear conditioning paradigm and observed a similar deficit in extinction retention to

Please cite this article in press as: Milad, M. R., et al., Neuroscience of fear extinction: Implications for assessment and treatment of fear-based and anxiety related disorders, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.08.006

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that observed in PTSD (Milad et al., 2013), further supporting our proposition that fear extinction may be deficient across the different anxiety disorders even in the case of OCD, which may not fit the fear learning model like PTSD. However, PTSD is no longer officially categorized as an anxiety disorder in the psychiatric nomenclature (Association, 2013). Moreover, in OCD, we observed a dysfunction in the vmPFC functional activation during extinction recall, much like in PTSD (Milad, Pitman, et al., 2009; RougemontBucking et al., 2011), but a different pattern of dysfunctional activations in the dACC and other brain regions compared with PTSD. Thus, while additional research is needed to clarify differences and similarities in fear extinction abnormalities and their associated neurocircuitry across the anxiety and trauma-related conditions and their specific symptom profiles, initial evidence suggests this circuit is implicated across anxiety conditions and may be a core feature underlying their related psychopathology as well as their high degree of comorbidity. Such findings have clear parallels for phobic anxiety disorders such as PD; while a specific traumatic experience is not inherent to the condition, symptoms of PD include fear of somatic sensations, panic attacks and negative consequences of panic. Further, those with PD and agoraphobia develop fear and avoidance of specific situations or contexts associated with panic or anxiety sensations. Similarly, in SAD, patients fear catastrophic negative outcomes in response to performance situations or social interactions, and avoid contexts that trigger these anxious responses. Finally, while generalized anxiety disorder (GAD) may be the least clear example of a fear conditioningrelated disorder, psychological theories have implicated intolerance of emotion and fear and avoidance of aversive psychological experiences as core to GAD psychopathology (Mennin, Heimberg, Turk, & Fresco, 2005; Roemer, Salters, Raffa, & Orsillo, 2005). Therefore, more research is needed to understand the role of abnormalities in fear extinction in GAD. Does the functional integrity of this circuit change with treatment? There are several key questions that cognitive and basic neuroscience strives to answer. For example, to what degree do current therapeutic approaches (pharmacological or behavioral) restore functional activity within affected brain regions in patients to levels that are comparable to normal controls? Are there differences in the functional activation of nodes specifically involved in fear extinction and emotion regulation in general after pharmacotherapy versus behavioral therapy? Could functional activation of key brain regions predict treatment outcome? Are these differential activations due to an innate vulnerability or are they acquired over a lifetime. The answers to these questions generally remain elusive as not all patients who undergo current treatments benefit from them equally. The development of biologically-based, targeted approaches could help determine how a given therapy affects the neural networks mediating fear and anxiety. Gaining a greater understanding of the mechanism of action of such a treatment could then inform future refinement of existing therapies as well. Improving the prediction of treatment outcome based on specific underlying neurobiological abnormalities and their interaction with specific treatment approaches could help clinicians select the therapeutic regimen with the greatest potential for a given patient, which would lead to more personalized, efficient and effective care. There are several published reports that begin to provide some answers pertaining to prediction of treatment outcome with respect to anxiety disorders. This relatively small volume of studies is well summarized in a recent review by Shin, Davis, Vanelzakker, Dahlgren, & Dubois (2013). Briefly, several studies have used PET resting state, measures of structural integrity,

and functional MRI in concert with a variety of tasks across PTSD, OCD, GAD, and SAD. The majority of these studies highlight the role of different subregions of the prefrontal cortex, along with the amygdala in some cases, as having predictive power for treatment outcome (summarized in (Shin et al., 2013)). For example, Falconer et al. reported that greater activation in prefrontal regions induced by a go/no go task predicted lower PTSD symptoms after treatment with cognitive behavioral therapy (CBT) (Falconer, Allen, Felmingham, Williams, & Bryant, 2013). Another study showed that the BDNF Val66Met genotype predicted recovery from PTSD after CBT (Felmingham, Dobson-Stone, Schofield, Quirk, & Bryant, 2013). Available data examining the structural integrity of the fear extinction network in patients with PTSD show that lower PTSD symptoms after CBT was predicted by larger vmPFC volume (Bryant et al., 2008). Studies testing the changes in the structural and functional correlates from pre-to post-treatment are lagging, and much research is needed in this domain. Nonetheless, the studies reviewed above provide some very encouraging initial data indicating that the development of biological markers for treatment outcome may be an attainable objective within the next decade. How this line of research has been translated to the clinic? In addition to predicting treatment outcomes and examining the mechanism of change induced by exposure- and behavioralbased therapies, understanding the mechanisms of fear extinction could help develop novel therapeutic approaches to treat anxiety disorders. Based on the understanding that extinction learning induces a new form of memory (CS- No-US association) (Bouton, 2002; Bouton & Moody, 2004; Milad et al., 2006), and that exposure-based therapy may rely on mechanisms that are shared with fear extinction learning, investigators began to explore ways in which exposure-based therapies may be augmented, in order to reduce the amount of time/sessions needed to achieve a reduction in symptoms and to reduce relapse after remission (Lee, Kwon, Choi, & Yang, 2007; Ressler et al., 2004). Ressler et al. were the first to translate this idea to a clinical population. After discovering that a drug known as D-cycloserine (DCS) could enhance fear extinction in rodents, Ressler et al. administered DCS to a cohort of patients diagnosed with height phobia while undergoing exposure therapy. This groundbreaking study was the first to show that patients receiving DCS showed a significantly faster rate of extinction compared to patients taking placebo pills (Ressler et al., 2004). DCS acts as a partial NMDA-receptor agonist, increasing excitatory binding of NMDA in the BLA. When injected into the hippocampus, DCS also enhances the expression of the NR2B protein, a subunit in the NMDA receptor (Davis, Ressler, Rothbaum, & Richardson, 2006; Ren et al., 2013). Extending these very encouraging data beyond height phobia, Hoffman et al. reported a significantly greater reduction of symptoms in patients with SAD using DCS compared to pill placebo taken prior to exposure therapy sessions (Hofmann, Pollack, & Otto, 2006). Wilhelm et al. extended those findings to OCD, and Otto et al., 2010 applied them to a shortened 5 session CBT intervention for PD (Otto et al., 2010). Despite these very exciting initial reports on the use of DCS, other studies have not been able to replicate or find the beneficial effects of DCS, in disorders such as in OCD (Storch et al., 2007). For example, a follow up, well-powered multicenter randomized controlled trial of DCS with a 12-week CBT intervention for patients with SAD found more rapid response, but no difference in response or remission compared to placebo, suggesting DCS may improve speed of response but not have significant additive benefit when a full course of CBT is delivered (Hofmann et al., 2013). For PTSD, the relatively small cohort of published studies yield inconsistent results. Litz et al. (2012) found that PTSD patients treated with DCS did significantly worse, with

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less reduction in PTSD symptoms compared to placebo. De Kleine et al. also did not report an overall effect of DCS on augmentation of exposure therapy but did report higher symptom reduction between therapy sessions in those with severe PTSD symptoms. In contrast, Difede et al. found strongly positive results with DCS augmentation of virtual reality based exposure in a pilot randomized trial of PTSD (de Kleine, Hendriks, Kusters, Broekman, & van Minnen, 2012; Difede et al., 2014). Of note, two studies in SAD and specific phobia found that the success of a given exposure session may also moderate the effectiveness of DCS (Smits, Rosenfield, Otto, Marques, et al., 2013; Smits, Rosenfield, Otto, Powers, et al., 2013), Another brief intervention for acrophobia found no effect when DCS was delivered post exposure (Tart et al., 2013). In a rodent model, investigators found DCS to augment fear extinction, but nevertheless left the fear memory intact, leading to no differences in renewal the following day irrespective of drug treatment (Woods & Bouton, 2006). Further studies suggest that the beneficial effect of DCS on extinction may be specific to the context in which extinction is learned, as the drug did not prevent fear renewal in the original conditioning context (Bouton, Vurbic, & Woods, 2008). This, therefore, remains a very active area of research that is aiming to understand some of the apparent negative and discrepant results regarding the use of DCS augmentation of exposure to reduce symptoms of anxiety disorders. Nonetheless, this is an excellent example of the direct translation of findings from the preclinical work elucidating the basic neuroscience of fear extinction to the clinic, as well as the benefits of increasing the dialog between neuroscience and the fields of psychology and psychiatry. What's around the corner? Many investigators have begun to explore other pharmacological agents that could facilitate fear extinction in rodents, and that could potentially be used in humans with minimal to no side effects. Some of these agents have already begun being tested in clinical trials including methylene blue and yohimbine, both of which have been shown to facilitate fear extinction in rodents (Gonzalez-Lima & Bruchey, 2004; Holmes & Quirk, 2010). Methylene blue is thought to improve extinction memory retention by increasing mitochondrial activity in the brain (Telch et al., 2014), whereas Yohimbine, a noradrenaline agonist, is thought to enhance emotional memories by elevating noradrenaline levels (Meyerbroeker, Powers, van Stegeren, & Emmelkamp, 2012). The initial results with yohimbine are mixed (Smits, Rosenfield, Davis, et al., 2014), but a great deal remains to be examined regarding the potential use of these agents to treat anxiety disorders. Further, this model of brief delivery associated with enhanced extinction learning provides a stark contrast to the common practice of long term pharmacotherapy with antidepressants, or the common use of chronic or as needed benzodiazepines which may interfere with extinction learning (e.g. Hart, Panayi, Harris, & Westbrook, 2014). Recent studies, for example, are beginning to highlight the potential of estrogen used as adjunct to exposure therapies (LebronMilad & Milad, 2012), given that estrogen has been shown to enhance extinction memory consolidation and increase the activation of the fear extinction network in female rodents and in women (Chang et al., 2009; Milad, Igoe, Lebron-Milad, & Novales, 2009; Milad et al., 2010; Zeidan et al., 2011) and that low levels of estrogen (either naturally or induced by use of oral contraceptives) are associated with low levels of fear extinction (Graham & Milad, 2013). It is an exciting time with growing translation from the laboratory to the clinic, with other potentially intriguing pharmacological targets for enhancing extinction learning under consideration.

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In addition to the use of pharmacological agents, recent advances in neurotherapeutics are beginning to highlight the potential usefulness of device-based approaches to reduce fear and anxiety symptoms common across mood and anxiety disorders as well (Rodman et al., 2012). These devices include deep-brain stimulation (DBS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS). The use of these stimulation devices has already been shown some promising data in MDD, and OCD as well as in PTSD (Marin, Camprodon, Dougherty, & Milad, 2014). The use of these devices is not currently implemented in practice to augment the effects of exposure-based therapies. We have recently proposed that future studies could be used to allow the application of data related to fear extinction as a guide for the use of these devices in such way that would allow their concurrent use with exposure-based therapies (Marin et al., 2014). The objective of this approach would be to combine two effective treatments in a targeted evidence-based fashion to achieve a significant synergistic effect of their combined use in appropriate patients. The development of optogenetics has shown tremendous promise in recent years allowing the direct stimulation of neural circuitry. Briefly, optogenetics uses genetically modified neuronal cells that respond to light (Adamantidis, Zhang, de Lecea, & Deisseroth, 2014). By stimulating the light-sensitive proteins implanted in the target cells, researchers can modulate and record neuronal activity in living tissue. Early demonstrations of the efficacy of optogenetics (Boyden, Zhang, Bamberg, Nagel, & Deisseroth, 2005) have been greatly expanded upon and researchers are now targeting fear circuitry. For example, in rodents, researchers have shown that stimulation of BLA terminals in the central nucleus of the amygdala has an acute anxiolytic effect (Tye et al., 2011). Optical activation of lateral amygdala pyramidal neurons has helped validate the hypothesis that associative fear learning is gated by their stimulus-induced activation (Johansen et al., 2010). Conclusion Data gathered from basic and translational studies in the neuroscience of fear extinction have only recently begun to influence how these disorders are identified, understood, and treated. While early challenges and questions about the validity of the model may have delayed translation to clinical applications, it is becoming increasingly clear that developments in pharmaceutical and devicebased therapies that target the fear extinction network may be very useful for breaking the impasse we currently have regarding the assessment and treatment of anxiety and mood disorders. Moreover, translational research in the area of fear extinction could help guide the development of future research, including a broader understanding of how fear extinction relates to the spectrum of anxiety disorders, not solely those associated with a specific fear. An increased dialog between clinicians and researchers will hopefully yield novel therapies, as more studies meld imaging and psychophysiological data with clinical, psychometric and demographic data. This approach will become even more valuable, in light of the recent pivot toward outcomes based research, evidence based practice, and the greater emphasis on translational research. References Adamantidis, A. R., Zhang, F., de Lecea, L., & Deisseroth, K. (2014). Optogenetics: opsins and optical interfaces in neuroscience. Cold Spring Harbor Protocols, 2014(8). http://dx.doi.org/10.1101/pdb.top083329. pdb top.083329. Asami, T., Hayano, F., Nakamura, M., Yamasue, H., Uehara, K., Otsuka, T., et al. (2008). Anterior cingulate cortex volume reduction in patients with panic disorder. Psychiatry and Clinical Neurosciences, 62(3), 322e330. http://dx.doi.org/10.1111/ j.1440-1819.2008.01800.x. PCN1800 [pii].

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Please cite this article in press as: Milad, M. R., et al., Neuroscience of fear extinction: Implications for assessment and treatment of fear-based and anxiety related disorders, Behaviour Research and Therapy (2014), http://dx.doi.org/10.1016/j.brat.2014.08.006