Review Imp

Neurobiology of Learning and Memory xxx (2013) xxx–xxx

Contents lists available at ScienceDirect

Neurobiology of Learning and Memory

journal homepage: www.elsevier .com/ locate/ynlme

Review

From Pavlov to PTSD: The extinction of conditioned fear in rodents,humans, and anxiety disorders

1074-7427/$ - see front matter � 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.nlm.2013.11.014

Abbreviations: 5-HTTLPR, serotonin transporter gene linked polymorphicregion; BDNF, brain-derived neurotropic factor; BNST, bed nucleus of the striaterminalis; COMT, catechol-O-methyltransferase; CR, conditioned response; CS+ orCS, conditioned stimulus; CS�, never-conditioned stimulus; dACC, dorsal anteriorcingulate cortex; DAT1, dopamine active transporter gene; DCS, D-cycloserine;DRD2, dopamine receptor D2 gene; EMG, electromyography; fMRI, functionalmagnetic resonance imaging; GABA, gamma-aminobutyric acid; HRR, heart rateresponse; IED, improvised explosive device; NMDA, N-methyl-D-aspartate; NPSR1,neuropeptide S receptor; OCD, obsessive–compulsive disorder; PET, positronemission tomography; PTSD, posttraumatic stress disorder; rCMRglu, regionalcerebral metabolic rate for glucose; SCR, skin conductance response; SRI, serotoninreuptake inhibitor; TMS, transcranial magnetic stimulation; TPH2, tryptophanhydroxylase-2; US, unconditioned stimulus; UR, unconditioned response; vmPFC,ventromedial prefrontal cortex.⇑ Corresponding author at: Tufts University Psychology, 490 Boston Avenue,

Medford, MA 02155, USA.E-mail address: [email protected] (M.B. VanElzakker).

Please cite this article in press as: VanElzakker, M. B., et al. From Pavlov to PTSD: The extinction of conditioned fear in rodents, humans, anddisorders. Neurobiology of Learning and Memory (2013), http://dx.doi.org/10.1016/j.nlm.2013.11.014

Michael B. VanElzakker a,b,⇑, M. Kathryn Dahlgren a,b, F. Caroline Davis b, Stacey Dubois a, Lisa M. Shin a,b

a Tufts University Psychology, 490 Boston Avenue, Medford, MA 02155, USAb Massachusetts General Hospital Psychiatry, 149 Thirteenth Street, Charlestown, MA 02129, USA

a r t i c l e i n f o a b s t r a c t

Article history:Received 1 August 2013Revised 31 October 2013Accepted 24 November 2013Available online xxxx

Keywords:Fear extinctionFear conditioningPosttraumatic stress disorderAnxietyTreatmentAmygdalaPrefrontal cortex

Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict abiologically relevant event: after repeated predictive pairings, Pavlov’s dogs were conditioned to antici-pate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologicallyrelevant, and neutral cues can take on great salience when they predict a threat to survival. In anxietydisorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish,and reminders of traumatic events can cause pathological conditioned fear responses for decades afterdanger has passed. In this review, we use fear conditioning and extinction studies to draw a direct linefrom Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuro-imaging studies of healthy humans and humans with PTSD. We describe several genes that have beenlinked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear condi-tioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drugand neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders.

� 2013 Elsevier Inc. All rights reserved.

1. Introduction

In his classical conditioning and extinction experiments, IvanPavlov rang a bell (the conditioned stimulus; CS), immediatelybefore giving his dogs food (specifically meat powder, the uncondi-tioned stimulus; US; Pavlov, 1927). On its own, the meat powdermade the dogs salivate (the unconditioned response; UR). Afterrepeating this predictive pairing several times, Pavlov’s dogs begansalivating to the mere sound of the bell—even when no meat pow-der was presented—making salivation the conditioned response

(CR). The sound of the bell predicted something agreeable and bio-logically valuable: food. However, not all of Pavlov’s USs werepleasant, and not all CRs conveyed his dogs’ anticipation of some-thing enjoyable. In addition to learning about nourishmentsources, it is important for an organism to be able to predict threatsto health and safety. For example, when Pavlov repeatedly pairedthe sound of a metronome (CS) with subsequent application of asmall amount of sour-tasting diluted acid (US) onto a dog’s tongue,the dog eventually learned the association. Henceforth, upon pre-sentation of the CS alone, the dog exhibited what Pavlov called a‘‘defensive reflex’’: it shook its head, salivated profusely, andmoved its tongue as if to expel a toxic substance, even though noacid was there. A similar process was demonstrated with an11-month-old child in Watson and Rayner’s famous ‘‘Little Albert’’experiments of 1920. Watson and Rayner paired Albert’s touchingof a white rat (CS) with a sudden fear-arousing noise (US) made bystriking a steel bar behind him (Watson & Rayner, 2000). Uponsubsequent presentations of the rat, Albert no longer exhibitedhis natural curiosity, but rather withdrew his hand. This learnedresponse seemed to generalize to cotton balls, a Santa Claus mask,a brown bunny, and a black fur coat. The Little Albert experiment isan early precursor of what is now known as fear conditioning.

It is not known whether Little Albert subsequently experiencedfear around rats and furry objects (if he survived into adulthood atall) or if he was healthy and well-adjusted (Harris, 2011). Ofcourse, modern ethical standards would not allow such a

anxiety

2 M.B. VanElzakker et al. / Neurobiology of Learning and Memory xxx (2013) xxx–xxx

methodology. Still, it is likely that, after the experiment was over,Little Albert encountered other rats or other furry objects in theabsence of a loud noise. Eventually, he should have learned thatsuch objects no longer predicted a frightening clang, and his fearresponse should have declined. This process is known as fearextinction learning. When the CS no longer predicts the US, theconditioned fear response is extinguished.

How do these processes of fear conditioning and fear extinctionwork? Why is it that with very severe USs, some individuals areburdened by fear and anxiety for decades? The goal of this reviewis to examine the underlying mechanisms and neurocircuitry offear conditioning and extinction, as well as to explore how theseprocesses can inform our understanding of anxiety disorders suchas posttraumatic stress disorder (PTSD). We will first discuss fearconditioning and extinction in rodents, and then in healthyhumans. Finally, we’ll discuss fear conditioning and extinction inindividuals with PTSD and other anxiety disorders, with an empha-sis on how extinction learning relates to treatment.

2. Fear conditioning in rodents

When rodents sense danger, one species-specific behavioralresponse is to freeze all movement in order to avoid detection bypredators. Rodent fear conditioning and extinction studiestypically use a foot shock as the US. The fear response is operation-alized as the percentage of time a rodent spends engaging in freez-ing behavior. When a light or tone (CS) repeatedly predicts a footshock (US) delivered through an electrified metal cage floor,rodents are conditioned to make a CS–US association. Thus, thepresence of the CS subsequently triggers freezing, which becomesthe CR. Furthermore, when a rodent experiences an aversive USsuch as shock in a certain context, subsequent re-exposure to thatcontext can cause freezing behavior, even if the shock has not beenpaired with a discrete CS such as a light or tone. This type of Pav-lovian fear conditioning is known as contextual fear conditioning(Rudy, Huff, & Matus-Amat, 2004). When a rodent experiences asudden loud noise it will startle before freezing, but if that suddenloud noise occurs during the presentation of a danger-associatedcue such as a CS or a conditioning context, the startle reflex willbe larger. This is known as a fear-potentiated startle and is anothercommonly used CR (Davis, 2001, chap. 8). The fear-potentiatedstartle paradigm is advantageous for translational researchbecause it is not species-specific.

Researchers can link conditioned behaviors such as freezing orfear-potentiated startle to brain activity or other fear-based phys-iological measures. With this simple fear conditioning model, theneurocircuitry of fear learning and extinction has been well delin-eated (reviewed in more detail in this issue and also Johnson,McGuire, Lazarus, & Palmer, 2012; LeDoux, 2000; Maren, 2001;Rudy, 2008). Here, we will briefly review the neurocircuitry in-volved in fear conditioning and extinction in rodents (see Fig. 1).

The sensory experiences of the CS and US are processed in thethalamus and somatosensory cortex, as are other sensory experi-ences. This information reaches the lateral amygdala via one oftwo routes. A ‘‘cortical pathway’’ relays detailed sensory informa-tion through the thalamus to the neocortex and hippocampusbefore integration and evaluation in the lateral amygdala. How-ever, another pathway forgoes the neocortex in the service of reac-tion speed. This faster ‘‘subcortical pathway’’ projects arudimentary sensory representation directly from thalamus tothe lateral and central nuclei of the amygdala. The binding togetherof a conditioned CS–US association is supported by the lateral nu-cleus of the amygdala, which then projects to the central amygdala,triggering autonomic and behavioral responses such as freezing(Blair, Schafe, Bauer, Rodrigues, & LeDoux, 2001; Pitkanen, 2000)

Please cite this article in press as: VanElzakker, M. B., et al. From Pavlov to Pdisorders. Neurobiology of Learning and Memory (2013), http://dx.doi.org/10.10

and fear-potentiated startle (Campeau & Davis, 1995). The amyg-dala is part of a broader neurocircuitry that supports and modu-lates this process.

Conditioning and extinction of rodent freezing behavior areboth modulated by medial prefrontal cortex (mPFC) structures.The more dorsal prelimbic cortex of the rodent is associated withthe expression of conditioned fear (Burgos-Robles, Vidal-Gonzalez,& Quirk, 2009). The prelimbic cortex acts as a fear response ‘‘accel-erator’’ during conditioning, while the more ventral infralimbiccortex acts as ‘‘brakes’’ during extinction. The infralimbic cortexis necessary for fear conditioning responses to context (Resstel,Joca, Guimarães, & Corrêa, 2006), probably due to its connectivityto hippocampus and amygdala (Bouton, Westbrook, Corcoran, &Maren, 2006; Maren, Phan, & Liberzon, 2013).

The hippocampus serves the function of binding together thedisparate sensory and interoceptive elements that form a contextinto one conjunctive representation (Rudy & O’Reilly, 2001). Therodent hippocampus has connections with both prelimbic andinfralimbic cortex and thus provides contextual modulation overfear responses. Furthermore, during exploration of the environ-ment, the hippocampus, along with associated medial temporalcortex, serves as a functional comparator of present and past(stored) experience (VanElzakker, Fevurly, Breindel, & Spencer,2008). As such, it is vital to the recognition of a context as familiaror the establishment of a context as novel. A related function is itsinvolvement in comparing novel cues to an existing CS, to deter-mine if a CR is appropriate; stimulus generalization is what led Lit-tle Albert to be wary of cues that only moderately resembled awhite rat. The hippocampus is therefore a crucial structure indetermining whether contextual cues are associated with dangeror with safety (Maren, 2013; Rudy et al., 2004).

2.1. Extinction in rodents

At the level of behavioral observation, if a conditioned cue (CS)or context is repeatedly presented without subsequent shock (US),the rat will stop freezing in response to the CS. This process ofextinction is somewhat tenuous, as its recall is fundamentally con-text-dependent (Bouton, 2004; Bouton, Westbrook, et al., 2006).That is, once both a CS–US (conditioning) and a CS–noUS (extinc-tion) representation exist, the response relevant to CS–noUS is onlyexpressed in the context in which CS–noUS was learned. Further-more, reduction of the CR does not necessarily mean that theCS–US association has been broken. This is demonstrated by thephenomena of spontaneous recovery, reinstatement, and renewal.As Pavlov described, spontaneous recovery refers to the fact that,after the passage of time, the CS can recover the ability to elicitan extinguished CR. Reinstatement of an extinguished CR occurswhen the US is presented in the absence of the CS; simple exposureto a US, even outside of the conditioning or extinction context orwithout being paired with any particular cue, can reinstate fearresponses to a previously conditioned context or cue. More recentrodent research has also revealed the phenomenon of renewal,which occurs when conditioning and extinction occur in differentcontexts: a change from the extinction context either back to theconditioning context or into a third context can cause the CR to re-new (Bouton, 2004). Therefore, while it may be intuitive to con-clude that extinction of the CR represents a fading away of theCS–US association, these three phenomena provide evidence thatfear extinction primarily represents a competing memory (Herryet al., 2010) because the CS can still recover the ability to cause aCR without ever being re-paired with the US. This demonstratesthat extinction learning represents a new CS–noUS memory tracethat competes with and inhibits the existing CS–US memory.

So if extinction represents new learning, how can it give rise toinhibition over a prepotent fear response? There is evidence to

TSD: The extinction of conditioned fear in rodents, humans, and anxiety16/j.nlm.2013.11.014

Fig. 1. A simplified schematic of fear neurocircuitry, showing functional homology of rat and human brain regions. PL in rat and dACC in human are homologues, both projectto the lateral nucleus of the amygdala. IL in rat and vmPFC in human are homologues, both project to the basal nucleus and to intercalated cells of the amygdala. The circuitrywithin the amygdala is shared among species. Arrowheads represent excitatory projections and circle-endings represent inhibitory projections. Within the amygdala, greenshapes represent glutamatergic (excitatory) cells and red shapes represent GABAergic (inhibitory) cells. Projections from lateral nucleus to CeL, from basal nucleus to CeM,and some other connections are not shown. Abbreviations: CeL = centrolateral subdivision; CeM = centromedial subdivision; dACC = dorsal anterior cingulate cortex;H = hippocampus; IL = infralimbic cortex; ITC = intercalated neurons; PL = prelimbic cortex; SC = somatosensory cortex; T = thalamus. (For interpretation of the references tocolor in this figure legend, the reader is referred to the web version of this article.)

M.B. VanElzakker et al. / Neurobiology of Learning and Memory xxx (2013) xxx–xxx 3

suggest that there is a necessary excitatory component to thisprocess of fear response inhibition: in rodents, blocking NMDAreceptors (N-methyl-D-aspartate, a receptor for the excitatoryneurotransmitter glutamate) impairs extinction (Davis, 2011;Zimmerman & Maren, 2010). The rodent infralimbic cortex hasdirect, excitatory projections to the amygdala’s intercalated neu-rons (Berretta, Pantazopoulos, Caldera, Pantazopoulos, & Paré,2005), a group of GABA (gamma-aminobutyric acid, an inhibitoryneurotransmitter) producing cells with inhibitory influence onamygdala output. These neurons project to the central amygdala,representing the extinction association (CS–noUS) as a counteringinfluence against the excitatory projections from the lateral nu-cleus that represent the conditioned association (CS–US). Indeed,excitation of infralimbic cortex during presentation of a CS (Milad& Quirk, 2002) or in a fear context (Thompson et al., 2010) causesextinction. Thus, extinction of conditioned fear responses repre-sents inhibition of the central amygdala output neurons thatcontrol freezing or startle behavior via their projections to themidbrain (Amano, Unal, & Paré, 2010). The infralimbic cortex isalso involved in fear extinction recall (Milad & Quirk, 2012).Studies in mice have demonstrated that distinct neurons in thebasal nucleus of the amygdala appear to encode the differentialconditioning memory and extinction memory (Herry et al., 2008).

2.2. Reconsolidation

Although the focus of this review is on extinction, we shouldalso mention the phenomenon of memory reconsolidation. Whena CS+ is presented after conditioning, the fear memory is reacti-vated, enters a labile state, and is open to (1) reconsolidation or(2) reconsolidation blockade using either a pharmacologic agent(e.g., Gamache, Pitman, & Nader, 2012; Kindt, Soeter, & Vervliet,2009; Nader & Hardt, 2009; Nader, Schafe, & Le Doux, 2000;Pitman et al., 2011) or immediate extinction within the labilitywindow (e.g., Monfils, Cowansage, Klann, & LeDoux, 2009). Re-peated reconsolidation over a long period of time is thought to


strengthen the fear memory (Parsons & Ressler, 2013), whereasreconsolidation blockade immediately after fear memory retrievalcan diminish it. In short, decreasing the CR could be achieved viaeither extinction or reconsolidation blockade, although the lattermay be most successful when fear memories are relatively new(Milekic & Alberini, 2002).

To summarize rodent studies of fear conditioning and extinc-tion, the amygdala is a key structure for recognizing salient cuessuch as potential threats and their predictors, and for mobilizingbehavioral fear responses (Davis & Whalen, 2001). Amygdalar out-put is modulated by the neocortex, especially by the differentialprojections of the prelimbic and infralimbic regions of the medialprefrontal cortex (Vertes, 2004). In rodents, the prelimbic cortexprojects to the lateral amygdala and activity in this region is asso-ciated with learning the CS–US predictive pairing during fear con-ditioning. The infralimbic cortex, in contrast, projects to theinhibitory intercalated neurons and serves to reduce fear after anew CS–noUS association is learned during extinction. When a fearmemory is reactivated, it is temporarily labile and vulnerable tomanipulation before reconsolidation. The phenomenology andneurocircuitry of fear conditioning and extinction revealed by ro-dent studies appear to be remarkably well preserved among otherspecies, including humans (Milad, Rauch, Pitman, & Quirk, 2006).

3. Fear conditioning and extinction in healthy humans

In human fear conditioning studies, the dependent measurequantifying fear (the UR or CR) is usually a psychophysiological re-sponse such as skin conductance response (SCR) or fear-potenti-ated startle. Functional neuroimaging studies frequently associateSCR with change in brain activity, but less frequently use fear-potentiated startle, as movement disrupts brain imaging. Thesestudies usually use a finger or wrist shock as the US and often com-pare a conditioned cue (CS+) to an unconditioned or extinguishedcue (CS�). Here, we briefly review the methods used in human fearconditioning and extinction studies and describe the basic findings,



first in psychophysiological studies and then in functional brainimaging studies.

3.1. Psychophysiological methods in humans

In humans, psychophysiological measures of the sympatheticnervous system response to fear or perceived threat most often in-clude SCR, electromyographic (EMG) response, or heart rateresponse (HRR). SCR is a method of measuring the perspiration-induced electrical conductance or moisture level of the skin,usually on the extremities (i.e. fingers, palms, or feet) and is themost widely used psychophysiological measure in fear condition-ing studies. EMG is a technique that records the electrical activityof skeletal muscles such as the orbicularis oculi (eyelid) or the cor-rugator supercilli (forehead). Studies of fear-potentiated startle inhumans most commonly use EMG to measure eyeblink responseor HRR. Heart rates can be measured through various meansincluding pulse oximetry. Electroencephalography (EEG) event-related potential (ERP) studies of conditioning and extinction inhealthy humans and PTSD have been reviewed elsewhere(Javanbakht, Liberzon, Amirsadri, Gjini, & Boutros, 2011; Pitmanet al., 2012), and will not be discussed here.

3.1.1. Psychophysiological findings in humansHealthy humans robustly demonstrate an increase in psycho-

physiological responses during fear conditioning (e.g., Cohen &Randall, 1984; Hamm & Vaitl, 1996). For example, during fear con-ditioning acquisition, SCR is higher in response to a CS+ relative toa CS� and is indicative of successful fear learning. Accelerated HRRhas also been demonstrated during fear conditioning acquisition,when the aversive stimulus is imminent (Hamm, Greenwald, Brad-ley, & Lang, 1993). Healthy human studies have also shown CS+potentiation of the startle reflex, relative to CS�s (Hamm et al.,1993; Lipp, Sheridan, & Siddle, 1994; reviewed in Grillon & Baas,2003). Furthermore, CS generalization can be demonstrated inhealthy humans by utilizing eyeblink as a measure of fear-potenti-ated startle responses (Lissek et al., 2008).

During extinction, psychophysiological responses to a CS de-crease as extinction learning progresses, and during extinction re-call, an extinguished CS is associated with significantly lower SCRthan an unextinguished CS (Milad, Orr, Pitman, & Rauch, 2005;Milad, Wright, et al., 2007). SCR is thus an inverse measure ofextinction recall.

An explicit safety signal is different than extinction because it isa cue that dependably signals that no US will be presented, asopposed to the gradual learning of a CS–noUS association thatcompetes with a CS–US association. However, both involve theinhibition of learned fear. Jovanovic and colleagues have utilizedfear-potentiated startle during a conditional discrimination para-digm (AX+/BX�) to assess the role of safety signals learning duringfear conditioning (reviewed in Jovanovic, Kazama, Bachevalier, &Davis, 2012). This paradigm was first developed in rats, demon-strating the translational appeal of fear-potentiated startle (Myers& Davis, 2004). In the adapted human paradigm, the US is a blast ofair to the throat and three different colored shapes (A, B, and X)serve as cues. The paradigm is called AX+/BX� because the US’spairing with X depends upon the presence of either A or B. A is athreat signal (like a CS) and B becomes a safety signal. In healthyhumans, a sudden loud noise during AX potentiates an eyeblinkstartle response, relative to a loud noise during BX or AB (Jovanovicet al., 2005). During this task, healthy control participants exhib-ited heightened fear potentiation under the AX condition. Duringa critical test phase, A is paired with B (without X). Healthy hu-mans show reduced fear-potentiated startle during this AB presen-tation, indicating successful learning of B as a safety signal andability to inhibit a learned fear response (Jovanovic et al., 2005).


3.2. Brain imaging methods in humans

Human fear conditioning and extinction neuroimaging studieshave replicated the basic neurocircuitry findings of rodent studies(for review, see Milad & Quirk, 2012; Rauch, Shin, & Phelps, 2006;Sehlmeyer et al., 2009). While human psychophysiological studiesmeasure SCR, HRR, or EMG as the CR, neuroimaging studies mea-sure brain activity. Three-dimensional images of ongoing brainfunction can be captured via functional magnetic resonance imag-ing (fMRI) or positron emission tomography (PET). Both methodsallow for simultaneous recording of some psychophysiologicalmeasures but because fMRI does not require injection of a contrastagent and has the ability to obtain functional and high-resolutionstructural images in the same session, it is the most commonlyused neuroimaging technique. Neither fMRI nor PET can achievethe cellular-level resolution of rodent studies that can utilize surgi-cally implanted electrodes to measure brain activity in a behavingrat. Furthermore, current functional neuroimaging methods areunable to differentiate between excitatory (glutamatergic) andinhibitory (GABAergic) processes (Heeger & Ress, 2002). However,the basic neurocircuitry is assumed to operate similarly within theamygdalae of rodents and humans (see Fig. 1 for a schematic ofshared amygdala circuitry).

During functional neuroimaging, participants are presentedwith sounds or pictures as CSs, and finger shocks or other aversivestimuli as USs. Because of the importance of context in fear condi-tioning and extinction studies, researchers need a way to manipu-late this variable (a neuroimaging environment is its own uniquecontext and cannot change during an experimental session). Tothis end, most groups display images of different settings (e.g.,an office room or a library) as a proxy for context, with a discreteCS either superimposed upon (e.g., a red X in the middle of thescreen) or embedded within (e.g., an illuminated red lamp in theroom) the context.

For example, Milad et al. have developed a two-day condition-ing and extinction paradigm in an fMRI scanner to study the brainbases of fear conditioning, extinction, and extinction recall in PTSD(Linnman, Zeffiro, Pitman, & Milad, 2011; Milad et al., 2009;Rougemont-Bücking et al., 2011). The methodology is as follows:Because rodent contextual fear conditioning studies havedemonstrated the importance of context pre-exposure (Rudy &O’Reilly, 2001), on day 1, participants are first pre-exposed toimages of two different rooms. The rooms are an office and alibrary, both featuring a lamp. Subsequent conditioning takes placein one of the contexts. During conditioning, two lamp colors (e.g.,blue and yellow, the CS+s) both predict finger shock approximately60% of the time, while another lamp color (e.g., red, the CS�) neverpredicts shock. After a short break, extinction of one of the CS+soccurs in a different ‘‘context’’ than conditioning. To ensure thatparticipants believe that a US might still be administered, theshock-delivery electrodes remain attached to participants’ fingersfor the remaining phases of the experiment. Participants areinstructed that they may be shocked, but the US is never againdelivered. Importantly, only one of the two CS+s (lamp colors) ispresented during extinction learning, allowing subsequent with-in-subjects comparisons among unextinguished CS, extinguishedCS, and the CS�. This comparison occurs the following day, duringextinction recall. Such methodology can be used to elucidate brainfunction during fear conditioning, extinction and extinction recallin healthy humans and in anxiety disorders such as PTSD.

3.2.1. Neuroimaging findings during conditioning in healthy humansIn accordance with the amygdala’s well-established role in fear

expression and learning in rodents, many neuroimaging studies ofhealthy humans have reported amygdala activation during fearconditioning (Alvarez, Biggs, Chen, Pine, & Grillon, 2008; Barrett



& Armony, 2009; Buchel, Dolan, Armony, & Friston, 1999; Buchel,Morris, Dolan, & Friston, 1998; Cheng, Knight, Smith, &Helmstetter, 2006; Cheng, Knight, Smith, Stein, & Helmstetter,2003; Cheng, Richards, & Helmstetter, 2007; Furmark, Fischer,Wik, Larsson, & Fredrikson, 1997; Gottfried & Dolan, 2004; Knight,Nguyen, & Bandettini, 2005; Knight, Smith, Cheng, Stein, &Helmstetter, 2004; LaBar, Gatenby, Gore, LeDoux, & Phelps, 1998;Lang et al., 2009; Linnman, Zeidan, Pitman, & Milad, 2013; Milad,Wright, et al., 2007; Morris & Dolan, 2004; Pine et al., 2001;Tabbert, Stark, Kirsch, & Vaitl, 2006). This amygdala activationco-occurs with increased SCR, which is evidence that amygdalaactivation is the neural correlate to the CR. The amygdala activatesto a CS that has been conditioned to complex USs such as aversiveimages or video clips (Doronbekov et al., 2005; Klucken et al.,2009) or conditioned to visceral USs such as lower gastrointestinalpain (Kattoor et al., 2013), as well as to a simple unconditioned USsuch as finger shock (Linnman, Rougemont-Bücking, Beucke,Zeffiro, & Milad, 2011). The amygdala also activates even whenthe CS is presented outside of conscious awareness (Critchley,Mathias, & Dolan, 2002; Knight, Waters, & Bandettini, 2009),and the resting-state functional connectivity of the human amyg-dala is altered after fear conditioning (Schultz, Balderston, & Helm-stetter, 2012).

For the purposes of comparing human and rodent fear condi-tioning and extinction studies, the human medial prefrontal cortex(mPFC) can be divided into dorsal and ventral structures. The dor-sal mPFC includes the dorsal anterior cingulate cortex (dACC),which is the likely human homologue of the rodent prelimbic cor-tex (see Fig. 1 for a schematic of rat and human mPFC homologuesprojecting to the same regions of the amygdala, which shares cir-cuitry across species). The ventral medial prefrontal cortex(vmPFC) is the likely homologue of the rodent infralimbic cortexand comprises several structures, such as the medial frontal gyrus(MFG), rostral anterior cingulate cortex (rACC), and subgenualanterior cingulate cortex (sgACC).

Fear conditioning or the expression of conditioned fear inhealthy humans has been associated with activity in medial pre-frontal brain regions such as dACC and vmPFC (Alvarez et al.,2008; Buchel et al., 1998, 1999; Klucken et al., 2009; LaBar et al.,1998; Lang et al., 2009; Maier et al., 2012; Marschner, Kalisch,Vervliet, Vansteenwegen, & Buchel, 2008; Milad, Quirk, et al.,2007; Milad, Wright, et al., 2007; Morris & Dolan, 2004; Phelps,Delgado, Nearing, & LeDoux, 2004). SCRs during conditioning arecorrelated with fMRI response in dACC and dACC thickness (Milad,Quirk, et al., 2007), and with the rate of resting metabolism indACC (Linnman et al., 2013).

Recent studies have reported hippocampal activation duringcontextual (Alvarez et al., 2008; Lang et al., 2009; Marschneret al., 2008) and simple cue (Buchel et al., 1999; Knight et al.,2004, 2009) fear conditioning in healthy humans. In a simulus gen-eralization study, Lissek et al. (2013) found that, as stimuli grewincreasingly different than a CS+, functional activation in the ven-tral hippocampus and vmPFC increased. As stimuli grew increas-ingly similar to a CS+, functional activation in the insular cortexincreased. In addition, several studies have found increased insularcortex activation during fear conditioning in healthy humans(Gottfried & Dolan, 2004; Klucken et al., 2009; Knight et al., 2009;Marschner et al., 2008; Morris & Dolan, 2004; Phelps et al., 2004).The insula also responds to paradigms (e.g., anticipatory anxiety)that elicit more sustained fear responses (Grupe, Oathes, & Nitschke,2013; Phelps et al., 2001; Somerville, Whalen, & Kelley, 2010). Thefear vs. anxiety distinction is discussed more in Section 4.1.

3.2.2. Neuroimaging findings during extinction in healthy humansSeveral studies of healthy humans have found extinction-asso-

ciated activation of the amygdala (Gottfried & Dolan, 2004; Milad,


Wright, et al., 2007; Phelps et al., 2004) and insula (Gottfried &Dolan, 2004; Phelps et al., 2004). As the CS gradually ceases to pre-dict the US during later stages of extinction learning, activation ofthe amygdala diminishes. Based upon rodent studies, this likely re-flects increased inhibitory influence from the intercalated neuronsof the amygdala, which is driven by the vmPFC. Indeed, as thehomologue to the rodent infralimbic cortex, the human vmPFC isassociated with increased activity during extinction learning(Barrett & Armony, 2009; Gottfried & Dolan, 2004; Kalisch et al.,2006; Linnman et al., 2012; Milad, Wright, et al., 2007) and duringextinction recall (Kalisch et al., 2006; Phelps et al., 2004). Duringextinction recall, vmPFC activation is positively correlated withSCR measures of extinction recall and also with hippocampus acti-vation, indicating a role for these brain regions in the contextualmodulation of fear extinction (Milad, Wright, et al., 2007). Re-cently, Linnman et al. (2012) found that resting-state metabolismin dACC is negatively correlated with extinction recall, and rest-ing-state metabolism in amygdala is positively correlated withfunctional dACC activation during extinction recall and negativelycorrelated with functional vmPFC activation during extinctionrecall.

In summary, functional neuroimaging studies have shown thatamygdala, dACC, and insular cortex activity are associated withfear conditioning and the expression of conditioned fear. Further-more, the hippocampus and vmPFC activate during conditioningin some studies, and may be involved in the processing of contex-tual information. During extinction learning, the vmPFC is acti-vated. Amygdala activity diminishes as the extinction associationis learned. During extinction recall, SCR is negatively correlatedwith vmPFC and hippocampal activation.

4. The fear conditioning model of PTSD

For decades, psychologists have theorized that pathologicalanxiety may reflect a failure to extinguish conditioned fear. Inthe 1970s, a ‘‘conditioning model of neurosis’’ emerged, which heldthat impaired extinction for certain CRs form the basis of anxieties,phobias, and compulsions (Eysenck, 1979; Pitman & Orr, 1986). In1980, PTSD became a formal diagnosis in the DSM-III and was con-sidered by many to be uniquely relevant to the conditioning frame-work because it is the only anxiety disorder to involve an explicitconditioning episode (i.e. the traumatic experience). Of course,the type of US that actually leads to PTSD is much more grievousthan the sudden loud noise that Little Albert experienced or themild finger shock delivered during the fMRI studies just described.And the conditioned fear response is much more debilitating,sometimes lasting decades after a traumatic experience. However,because the underlying processes appear to be similar, the fearconditioning and extinction framework has proven to be valuablein attempting to understand the mediating neurocircuitry andtreatment of PTSD (Holmes & Singewald, 2013).

PTSD is a severe anxiety disorder that affects approximately10–30% of individuals who have experienced or witnessed a psy-chologically traumatic event (de Vries & Olff, 2009; Dohrenwendet al., 2006; Weiss et al., 1992) such as sexual assault, combat, nat-ural disaster, motor vehicle accident, or witnessing the death orserious injury of another individual. Individuals with PTSD experi-ence three primary symptoms: (1) unwanted re-experiencing ofthe event, often in the form of intrusive memories and nightmares;(2) avoidance of reminders of the traumatic event, even in the ab-sence of real danger; and (3) ongoing hypervigilance, includingtrouble with sleep and concentration. Reminders of the traumaticexperience are particularly distracting and distressing to individu-als with PTSD (Hayes, VanElzakker, & Shin, 2012). While avoidanceand hypervigilance can occur in the absence of trauma-related



cues, re-experiencing events may be triggered by a previously neu-tral cue that was conditioned to the traumatic experience.

PTSD is frequently conceptualized as a memory disorder, withina Pavlovian fear conditioning and extinction framework (Elzinga &Bremner, 2002; Jovanovic & Ressler, 2010; Rubin, Berntsen, & Boh-ni, 2008; Shin & Handwerger, 2009). According to this framework,multiple cues become associated with a traumatic experience,forming strong sensory memories. This can occur in a manner thatPavlov demonstrated by simultaneously conditioning to a buzzer, ametronome, and tactile stimulation (Pavlov, 1927). Or it can hap-pen by stimulus generalization, like when Little Albert becamewary of objects that shared some trait with a white rat (the CS)whose presence predicted a loud, startling noise (Harris, 2011;Watson & Rayner, 2000). Multiple cues can be conditioned to thesame US and as we will review below (Section 5), PTSD is associ-ated with increased acquisition of fear conditioning. Furthermore,anxiety disorders are associated with increased propensity for CSgeneralization (Lissek et al., 2005). Therefore, it is likely that multi-ple cues would be capable of triggering a conditioned fear responsein a individual with PTSD. Upon encountering conditioned remind-ers, individuals with PTSD re-live their traumatic experiencethrough sensory memories. These memories are often disjointedand incomplete, with a disorganized and sometimes out-of-se-quence narrative (Brewin, 2011). This may reflect the diminishedsensory representations of the subcortical pathway discussed ear-lier (Fig. 1; Section 2; see also Pitman et al., 2012).

If PTSD symptoms emerge from a traumatically stressful condi-tioning episode, the failure to extinguish or maintain extinction ofthat conditioned fear allows symptoms to persist. For example,after the invasion of Iraq, US troops frequently faced improvisedexplosive devices (IEDs) hidden in trash piles along the side ofthe road. If a soldier survives an IED attack, this event forms a pow-erful memory and powerful associations. Ideally, such a veteranwho has returned to the United States should learn, upon severalexposures to trash piles along his street, that they no longer predictviolence. If this extinction fails to happen, then even years after thedanger has passed, a previously neutral cue (trash, the CS) that wasassociated with a grave danger (IED explosions, the US) may triggera fear response (CR) and painful memories. Indeed, even internalcues such as autonomic arousal or thirst can become CSs. For a vet-eran of war in Iraq, the CSs that cause a fear response could be thesight of a trash pile, the presence of a crowd of people, the feel ofhot temperatures under bright sunlight, the sound of Arabic beingspoken, the smell of diesel fuel from military vehicles, internalstates such as feelings of frustration, or any other cue that waspresent during the explosion. In his studies of multiple CSs, Pavlovreported that extinguishing one CS also extinguished the others,although subsequent research has found that this is not the caseand that extinction is cue-specific (Myers & Davis, 2007).

Although humans are only able to attend to approximately fourdiscreet cues at a time (e.g., Bettencourt & Somers, 2009), ourmemory of experiences normally feels rich and complete. Forexample, if you were asked where you were during breakfast thismorning, you could easily think of more than four details: thetastes and smells of the food, the table and chair where you sat,what you were wearing, what you ate, what you read or talkedabout while eating, and even how you felt are all details that youdid not plan on remembering, but were encoded into one episodicmemory (Rudy, 2009; Rudy & Tyler, 2010). Pavlov referred to thisas ‘‘dynamic stereotype’’—a neurological mapping of the environ-ment. This is what we mean when we refer to the ‘‘context’’ of amemory, including fear memories. The forming of such cognitiverepresentations of context is rapid and automatic. Context is a cru-cial variable that serves as something more than just another CSduring fear conditioning—it also acts as a safety signal after extinc-tion learning (reviewed in Bouton, Westbrook, et al., 2006; Maren


et al., 2013; Rudy, 2009). This means that extinction is particularlyinfluenced by the context in which it occurs (Bouton, García-Gut-iérrez, Zilski, & Moody, 2006).

For example, after a soldier comes back to the United States andrepeatedly sees innocuous trash piles, the association betweentrash and IEDs would ideally become extinguished, at least in thecontext of the United States. However, if that soldier were re-de-ployed to Iraq, the association between roadside trash and dangermight renew, because that association was appropriate in the con-text of occupied Iraq, and extinction learning did not occur in thatcontext. Thus, the process of fear extinction has been described as acontext-modulated form of inhibitory learning (Bouton, 2004). Inother words, because extinction learning forms a new association(CS–noUS) as opposed to ‘‘breaking’’ the conditioned CS–US associ-ation, extinction recall involves accessing competing CS associa-tions (CS–US vs. CS–noUS). Therefore, if extinction learning takesplace in a different context than conditioning, the CR becomes con-text-dependent. Just as an ambiguous word (e.g. ‘‘lead’’) is givenmeaning by context (i.e. ‘‘Metal weights are made of lead’’ vs.‘‘The winner of the race was in the lead from the start’’), the ambig-uous CS (a pile of trash) is given meaning by the context (suburbanUnited States vs. occupied Iraq).

However, context often does not serve as an effective safety sig-nal for individuals with PTSD. Even while in the United States, andeven after seeing innocuous trash piles many times, a veteran withPTSD may fail to extinguish the association between trash piles andIED explosions (CS–US). The CS continues to elicit a CR, namely dis-tressing sensory memories of an explosion. Empirical fear condi-tioning and extinction studies of this phenomenon will bediscussed in the next section (Section 5). Here, we relate renewal,spontaneous recovery, and reinstatement to the clinical presenta-tion of PTSD.

Exposure-based therapy is used in the treatment of PTSD and isconceptually based upon fear extinction. The phenomenon of re-newal (return of a CR in the conditioning context when extinctiontook place in a different context) is highly relevant to this type oftherapy. Exposure to progressively stronger trauma-related stimuliand memories (CSs) serves to create a new association betweenthose cues and safety (CS–noUS; Cukor, Spitalnick, Difede, Rizzo,& Rothbaum, 2009; Rothbaum & Davis, 2003). An individual mayspend hours in a therapist’s office, talking about his traumaticexperience in great detail, effectively extinguishing the CS–USassociation for any cues that remind him of the trauma. However,because extinction is context-specific, the CS–noUS associationarising from exposure therapy only exists in his therapist’s officeand not in other contexts. In other words, if fear conditioning tookplace in Iraq and fear extinction takes place in a therapist’s office,when an individual with PTSD is confronted with a now-ambigu-ous CS (e.g., trash) in a third context (e.g., a suburban street), theCS–US (trauma) association will beat out the CS–noUS (therapy)association. The CS–noUS fails to oppose the stronger, more salientCS–US association. This is the reason that therapists conduct ses-sions in multiple settings and use virtual reality to mimic multiplecontexts (e.g. Difede et al., 2007; Gerardi, Rothbaum, Ressler, Hee-kin, & Rizzo, 2008; Rothbaum et al., 1999). Extinction therapy andpharmacological enhancers of extinction will be discussed in moredetail below (Section 6.1).

Delayed onset PTSD, in which the emergence of symptoms doesnot occur until 6 months or more post-trauma (APA, 2000), occursin 8–25% of individuals with PTSD (Bryant, O’Donnell, Creamer,McFarlane, & Silove, 2013; Frueh, Grubaugh, Yeager, & Magruder,2009), and may be the clinical manifestation of the phenomenonof spontaneous recovery (the return of a CR after a long delay sinceits extinction). In contrast, reinstatement of the CR occurs when aUS is re-experienced, even when it is not paired with the CS. Thiscan manifest in PTSD patients who have a sort of ‘‘relapse’’ of



symptoms after successful therapy upon experiencing anotherstressful event. For example, Pitman (2011) described a WorldWar II veteran who had experienced nightmares and flashbacksfor 1 year after the war’s end. He was then symptom-free for30 years, until experiencing another highly stressful event (i.e., an-other US). The night after receiving a terminal cancer diagnosis, heexperienced nightmares again—but about combat, not cancer.

Fear conditioning paradigms provide a useful framework forstudying the canonical PTSD symptom of re-experiencing the trau-ma through powerful but disjointed memories upon exposure toany reminder. Although extinction failure can explain the persis-tence of trauma-related memories and distress in PTSD, reconsoli-dation also likely contributes. Repeated reactivation of traumaticmemories triggered by CSs can reconsolidate and strengthen them(Inda, Muravieva, & Alberini, 2011; Parsons & Ressler, 2013). How-ever, the fear conditioning model may not explain other PTSDsymptoms such as anxiety in the absence of trauma reminders (un-less stimulus generalization has occurred), or more complex cogni-tive and biological symptoms such as dissociation or endocrineabnormalities (reviewed in Zoladz & Diamond, 2013).

4.1. Fear vs. anxiety

Pavlovian fear conditioning paradigms that use a cue as a CSeffectively provoke the fear response, which is a phasic (discrete)response to a specific stimulus or event (e.g., a tone that predictsa shock). However, this paradigm might not appropriately modelthe ongoing anxiety in PTSD that leads to excessive hypervigilanceand avoidance of trauma reminders. Such anxiety has been concep-tualized as ‘‘sustained fear’’ and can instead be investigated usingparadigms that that put individuals into a general state of uncer-tainty, such as contextual (as opposed to cued) fear conditioningor paradigms that emphasize unpredictability (Davis, Walker,Miles, & Grillon, 2010). As detailed in Section 2, during contextualfear conditioning one learns to associate an aversive event (US)with a particular context rather than a distinct cue. The use ofcue conditioning vs. contextual conditioning paradigms has pro-vided insight into the neural basis of the overlap and distinctionbetween fear (discussed in more detail in earlier sections) and anx-iety. Both involve the amygdala, which responds to stimuli in theenvironment that predict biologically relevant events (Davis &Whalen, 2001). Autonomic and behavioral responses to both typesof paradigms are generated via projections from the amygdala tohypothalamic and brainstem targets (Davis et al., 2010). Researchsuggests that contextual fear learning is dependent on both theamygdala and hippocampus (Kim & Fanselow, 1992; Phillips &LeDoux, 1992). The sustained fear responses elicited by these par-adigms rely on the bed nucleus of the stria terminalis (BNST; re-viewed in Davis et al., 2010). The insula is also heavilyinterconnected with both the BNST and amygdala, and is involvedin producing sustained fear responses such as anticipatory anxiety(Grupe et al., 2013; Phelps et al., 2001; Somerville et al., 2010).

5. Conditioning and extinction in PTSD

5.1. Psychophysiological studies

As detailed in Section 3.1.1, psychophysiological measures are avaluable tool for assessing fear conditioning and extinction inhealthy humans. Researchers have also used these tools to explorefear conditioning and extinction abnormalities in PTSD (reviewedin Lissek et al., 2005; Pitman et al., 2012). Based upon that litera-ture, Guthrie and Bryant (2006) suggested that alterations inpsychophysiological responses that characterize PTSD during fearconditioning and extinction include (1) greater psychophysiologi-


cal response to USs; (2) greater psychophysiological responses dur-ing conditioning; and (3) higher continued psychophysiologicalresponses to CSs during extinction learning. We will focus on thelatter two points because the first is not as directly relevant to fearconditioning and extinction.

During the acquisition of conditioned fear, participants withPTSD exhibit larger differential (CS+ vs. CS�) SCR, EMG, and HRRresponses relative to individuals without PTSD (Blechert, Michael,Vriends, Margraf, & Wilhelm, 2007; Glover et al., 2011; Lisseket al., 2005; Orr et al., 2000; Peri, Ben-Shakhar, Orr, & Shalev,2000), although this increased response during acquisition hasnot been replicated in all studies (Glover et al., 2011; Milad et al.,2008, 2009).

Studies using SCR, EMG, and HRR also show heightened CRs inindividuals with PTSD during extinction learning (Blechert et al.,2007; Lissek et al., 2005; Orr et al., 2000; Peri et al., 2000) andnext-day extinction recall (Milad et al., 2008, 2009), consistentwith the idea that people suffering from PTSD have difficulty learn-ing and remembering that stimuli that used to predict threat nolonger do. Research using monozygotic twins discordant for com-bat exposure suggests that this extinction deficit may be an ac-quired characteristic of PTSD (Milad et al., 2008); however,reduced extinction learning before trauma exposure has also beenlinked to PTSD symptom severity after trauma exposure, whichsuggests that impaired extinction may be a vulnerability factorfor PTSD (Guthrie & Bryant, 2006).

Fear-potentiated startle paradigms have also proven to be auseful tool for exploring PTSD-related abnormalities in fear learn-ing and memory. For example, individuals with PTSD show ele-vated fear-potentiated startle responses in ‘‘threat’’ contexts(Grillon, Morgan, Davis, & Southwick, 1998; Morgan, Grillon,Southwick, Davis, & Charney, 1995). Fear-potentiated startle canalso be used to quantify fear during fear conditioning and extinc-tion paradigms. Such studies demonstrate that while individualswith PTSD are being conditioned, they exhibit enhanced fear-potentiated startle during the presentation of both CS+ and CS�during conditioning (Glover et al., 2011; Grillon & Morgan, 1999;Norrholm et al., 2011) and sustained fear responses to the CS+ dur-ing extinction (Norrholm et al., 2011). Interestingly, heightenedfear-potentiated startle to the CS+ predicted re-experiencingsymptoms (Glover et al., 2011; Norrholm et al., 2011) while height-ened fear-potentiated startle to the CS� predicted hyperarousalsymptoms (Glover et al., 2011). One study also found that an atten-tional bias towards threat sometimes reported in PTSD (reviewedin Hayes et al., 2012) was associated with increased fear-potenti-ated startle response to both CS+ and CS� during fear conditioningand extinction (Fani et al., 2012).

One explanation for the fact that individuals with PTSD showelevated fear responses to both CS+ and CS� is that they have animpaired ability to translate the presence of a safety signal intoinhibited fear responses (Jovanovic et al., 2012). Using the AX+/BX� conditional discrimination paradigm described in Section 3.1.1(Jovanovic et al., 2005), researchers learned that despite self-re-ports indicating that individuals with PTSD appropriately learnthat a particular cue (B) signals safety, they are still unable to inhi-bit their fear-potentiated startle response in its presence (Jovanov-ic et al., 2009). This manifested in an association betweenheightened fear-potentiated startle during the BX and AB trialsand PTSD symptom severity. This failure of individuals with PTSDto learn the ‘‘B’’ safety signal has been replicated, and in a subse-quent study, heightened fear-potentiated startle reactivity to ABtrials was associated with hyperarousal symptom severity(Jovanovic et al., 2010). These results, along with psychophysiolog-ical studies demonstrating impaired fear extinction, are consistentwith a general failure to inhibit learned fear, and may be an inter-mediate phenotype between the clinical symptoms of PTSD and



the dysfunctional neurocircuitry found in this disorder (Jovanovic& Norrholm, 2011).

5.2. Neuroimaging studies of PTSD

Psychophysiological abnormalities in conditioning and extinc-tion in PTSD are also reflected in neuroimaging studies. Comparedto healthy controls, individuals with PTSD show hyper-respon-sivity of brain regions associated with fear expression and condi-tioning, but hypo-responsivity of brain regions associated withfear extinction and extinction recall. Imaging studies have revealedabnormalities in PTSD at each stage of the fear conditioning andextinction paradigm. Essentially, in PTSD the fear ‘‘accelerators’’(amygdala and dACC) fail to turn off while the ‘‘brakes’’ (vmPFCand hippocampus) fail to turn on. These are the brain correlatesto the increased psychophysiological responses during condition-ing and extinction seen in PTSD. In the first neuroimaging studyof fear conditioning and extinction in PTSD, Bremner and col-leagues (2005) found that relative to healthy, non-abused femalecontrols, women with childhood sexual-abuse-related PTSDshowed greater left amygdala and dACC activation in the contrastbetween a fear acquisition condition (in which a shock to the fore-arm was predicted by a picture of a blue square) and a control con-dition (in which participants received random shocks with nopaired CS). During extinction, the PTSD group had relatively lessactivation in rACC and subgenual cortex. This study did not inves-tigate extinction recall or manipulate context.

As described earlier, Milad and colleagues have used a two-dayconditioning and extinction paradigm that manipulates context.Using this paradigm in an fMRI environment, this group has foundevidence that, in individuals with PTSD, structures that are in-volved in fear expression over-activate while structures involvedin fear inhibition under-activate or deactivate (Linnman, Zeffiro,et al., 2011; Milad et al., 2009; Rougemont-Bücking et al., 2011).Relative to the non-PTSD control group, the PTSD group had great-er amygdala activation to the US (a finger shock; Linnman, Zeffiro,et al., 2011). During late conditioning on day 1, they found in-creased dACC activation in PTSD, relative to the trauma-exposednon-PTSD control group (Rougemont-Bücking et al., 2011). Duringlate extinction on day 1, in a contrast of the extinguished CS+ ver-sus the never-conditioned CS�, the PTSD group had greater amyg-dala activation, suggesting that individuals with PTSD fail to learnfear extinction to the extent of trauma-exposed controls (Miladet al., 2009). On the following day, fear extinction recall was tested.The PTSD group exhibited relatively greater dACC activation andrelatively less activation in the hippocampus and vmPFC duringextinction recall. This implies that the regions responsible for iden-tifying the ambiguous CS as safe (hippocampus and vmPFC) failedto engage and the region responsible for identifying learned fearassociations (dACC) remained engaged. Thus, in PTSD, the hippo-campus may fail to differentiate safe from unsafe contexts afterextinction learning while the vmPFC fails to retain the extinctionof learned fear responses in the non-traumatic context.

5.3. Neurocircuitry model of PTSD

Interestingly, the finding of hyper-responsivity of the amygdalaand dACC and hypo-responsivity of vmPFC structures generalizesbeyond studies of fear conditioning and extinction (VanElzakker,Staples, & Shin, in press). For example, the amygdala is hyperre-sponsive in PTSD relative to control groups during trauma-related(Shin et al., 2004), trauma-unrelated emotional (Brohawn, Offringa,Pfaff, Hughes, & Shin, 2010) and emotionally neutral (Bryant et al.,2005) tasks. Likewise, the dACC is hyperresponsive relative to con-trols during trauma-related (Fonzo et al., 2013), trauma-unrelated


emotional (Hayes, LaBar, Petty, McCarthy, & Morey, 2009) andemotionally neutral (Shin et al., 2007, 2011) tasks.

Similarly, functional abnormalities in other fear conditioningand extinction-related brain structures point to a general neurocir-cuitry dysfunction in PTSD. Several studies using other tasks havereported significant negative correlations between vmPFC activa-tion and PTSD symptom severity (reviewed in Hughes & Shin,2011). This is evidence that reduced activation of vmPFC in PTSDis not specific to fear extinction learning and recall, but rather ap-pears to be a more general functional property of that brain region.In PTSD, the vmPFC also shows diminished activation or even deac-tivation relative to controls in response to reminders of trauma(e.g. Lanius et al., 2001; Shin et al., 1999), in tasks using emotionalbut trauma-unrelated stimuli such as facial expressions (e.g., Off-ringa et al., 2013; Williams et al., 2006), and even during emotion-ally neutral tasks (e.g., Moores et al., 2008).

Functional imaging studies of the hippocampus are mixed, withsome studies showing increased and some showing decreased acti-vation (Hughes & Shin, 2011). Type of task, type of stimuli (e.g.,trauma-related or -unrelated), and type of analysis may all beimportant factors in these inconsistencies. However, individualswith PTSD consistently have smaller hippocampi than controlgroups (Woon, Sood, & Hedges, 2010). This may be related to re-duced processing power for appropriate differentiation betweentrauma context and safe contexts. Furthermore, given its role incontextual, episodic, emotional, spatial, and declarative memoryprocesses (LaBar & Cabeza, 2006; Rudy, 2009; Rudy et al., 2004;Squire & Zola-Morgan, 1991), suboptimal hippocampus functionmay be related to the deficits in these processes seen in PTSD(Astur, St Germain, & Tolin, 2006; Bremner et al., 1999, 2003;Brohawn et al., 2010; Hayes et al., 2011; Shin & Liberzon, 2010).

Because PTSD is defined by a conditioning event, one may as-sume that these abnormalities emerge during the trauma or asPTSD emerges. However, another possibility is that this neurocir-cuitry represents a familial vulnerability factor that interacts witha traumatic experience to manifest PTSD symptoms. For example, astudy of monozygotic twins discordant for combat trauma sug-gested that a small hippocampus is a familial vulnerability factorfor PTSD (Gilbertson et al., 2002). Another recent twin study usingPET found that veterans with PTSD and their identical co-twins hadhigher resting-state regional cerebral metabolic rates for glucose(rCMRglu) in the dACC relative to the veterans without PTSD andtheir co-twins (Shin et al., 2009). Furthermore, rCMRglu in thecombat-unexposed twins was positively correlated with PTSDsymptom severity in their combat-exposed identical twins. Thisis evidence that resting-state dACC hyperactivity is a familial riskfactor for PTSD that may predate trauma exposure or PTSD. Twinand genetic studies have provided additional evidence that genesmay explain some of the relationship between PTSD and abnormal-ities in fear conditioning and extinction.

5.4. PTSD-related genes and fear extinction

A brain-based familial vulnerability to PTSD is likely to be atleast partially explained by genotype. Indeed, a study comparingSCRs of healthy monozygotic to healthy dizygotic twins demon-strated a moderate genetic contribution to fear conditioning andfear extinction (Hettema, Annas, Neale, Kendler, & Fredrikson,2003). Several PTSD-related genes have also been linked to abnor-mal fear conditioning and extinction in healthy humans and ro-dents, providing indirect evidence that the abnormalities in PTSDrevealed by the fear conditioning model may represent a vulnera-bility endophenotype (Amstadter, Nugent, & Koenen, 2009; Lons-dorf & Kalisch, 2011). PTSD-associated genes that are alsoimplicated in facilitated fear conditioning or attenuated extinctioninclude the serotonin transporter gene, dopamine-related genes,



and neuroplasticity-related genes (other genes are certainly in-volved; the genetics of PTSD are reviewed in Cornelis, Nugent,Amstadter, & Koenen, 2010; Digangi, Guffanti, McLaughlin, &Koenen, 2013; Pitman et al., 2012; Skelton, Ressler, Norrholm,Jovanovic, & Bradley-Davino, 2011 and the genetics of fear condi-tioning and extinction are reviewed in Johnson et al., 2012;Lonsdorf & Kalisch, 2011).

Genetic studies have found associations between PTSD and ashort (s) allele polymorphism that leads to low expression of theserotonin transporter gene (5-HTTLPR). A study of healthy individ-uals by Lonsdorf et al. (2009) used the fear-potentiated startleparadigm and found that 5-HTTLPR s-s and s-l (short-long) allelecarriers had larger potentiated conditioned startle responses, rela-tive to l-l allele carriers. Similarly, Garpenstrand, Annas, Ekblom,Oreland, and Fredrikson (2001) used SCR and also found enhancedconditioning in individuals with at least one 5-HTTLPR s-allele. An-other study investigated the social learning of fear conditioning(Cris�an et al., 2009). They found enhanced SCRs to a CS in s-allelecarriers who had observed another person undergo fear condition-ing, even though those participants never experienced a CS–USassociation themselves (Cris�an et al., 2009). Previous studies havefound associations between 5-HTTPLR and TPH2 (tryptophanhydroxylase-2, an enzyme that influences presynaptic serotoninsynthesis) ‘‘risk’’ genotype with PTSD and major depression(Bryant et al., 2010; Goenjian et al., 2012). Hermann et al. (2012)used fear conditioning and extinction within an fMRI environmentto study the influence of 5-HTTPLR and TPH2 genotype in healthyindividuals. They found that 5-HTTPLR risk genotype predicted in-creased activation in right insula to the US and to the CS during lateconditioning. 5-HTTPLR risk genotype interacted with childhoodadversity to predict increased amygdala activation during extinc-tion learning. TPH2 risk genotype interacted with childhood adver-sity to predict greater amygdala activation during conditioning andgreater vmPFC activation during extinction. Finally, a combinationof 5-HTTPLR and TPH2 risk genotypes predicted increased dACCactivation during extinction learning. Another recent study ofhealthy individuals examined the effect of 5-HTTPLR and neuro-peptide S receptor (NPSR1) genotype on contextual fear condition-ing and extinction in a virtual reality paradigm (Glotzbach-Schoonet al., 2013). They found that individuals with risk alleles in bothgenes exhibited higher fear-potentiated startle responses in theconditioned context relative to the ‘‘safe’’ context. NPSR1 genotypewas also associated with higher self-reported anxiety levels in theconditioned context, relative to the safe context. They did not findgenotype differences during extinction. These studies show a pat-tern of facilitated fear conditioning that carries over into extinctionin 5-HTTPLR risk allele carriers (reviewed in Lonsdorf & Kalisch,2011).

Several studies have found abnormal fear conditioning andextinction associated with dopamine-related genes. For example,Raczka et al. (2011) found that a polymorphism in the dopamineactive transporter 1 gene DAT1 predicted faster extinction learningin healthy humans. In a study of 60 healthy individuals, Huertaset al. (2010) found that a polymorphism in the DRD2 dopaminereceptor D2 gene predicted significantly attenuated SCR duringearly conditioning. The gene responsible for the enzyme cate-chol-O-methyltransferase (COMT) is related to synaptic availabilityof catecholamines such as dopamine and norepinephrine, espe-cially in the prefrontal cortex. COMT genotype predicted deficitsin extinction learning in healthy humans (Lonsdorf et al., 2009).A recent study showed that a COMT risk allele predicted higherfear-potentiated startle regardless of PTSD diagnosis (Norrholmet al., 2013). That same study found that in individuals with PTSD,the risk allele genotype predicted impaired fear inhibition to a CS�and was associated with DNA methylation status on four loci, twoof which were associated with the impaired fear inhibition.


Studies examining the relationship between the neuroplastici-ty-related brain-derived neurotropic factor (BDNF) gene and fearconditioning and extinction in healthy humans have been some-what mixed. Most BDNF studies have focused on one single-nucle-otide polymorphism (SNP): the Val66Met SNP, which substitutes avaline (Val) for methionine (Met) at codon 66. Hajcak et al. (2009)examined this SNP and found a significant genotype � stimulusinteraction in healthy individuals undergoing a fear-potentiatedstartle conditioning paradigm. Homozygous carriers of the Val al-lele had a significantly higher fear-potentiated startle response toa CS than Met-carriers. Similarly, Lonsdorf et al. (2010) found thatamong healthy individuals undergoing fear conditioning andextinction, Val-carriers showed increased conditioned fear-poten-tiated startle responses during late conditioning and early extinc-tion. In contrast to those two studies, Soliman et al. (2010) foundthat the Met allele predicted impaired extinction learning in miceand in healthy humans. Furthermore, in their study the Met allelewas associated with decreased vmPFC activation and increasedamygdala activation during extinction. Another study reportedinconsistent data in that homozygous Val-carriers showed height-ened SCR to both conditioned and unconditioned cues duringreconditioning of a previously extinguished association (Raczkaet al., 2011). Given the role of BDNF in hippocampal-dependentprocesses (Tyler, Alonso, Bramham, & Pozzo-Miller, 2002) as wellas fear and anxiety (Frielingsdorf et al., 2010), future researchmay emphasize contextual fear conditioning to better elucidatethe role of the Val66Met SNP of BDNF. Other neuroplasticity-re-lated genes may also be prime targets for PTSD-related fear condi-tioning and extinction research. For example, in mice, the stathmingene, an inhibitor of microtubule formation, and the Grp gene,which encodes gastrin-releasing peptide, are highly expressed inthe lateral nucleus of the amygdala and appear to be necessaryfor fear conditioning (Shumyatsky et al., 2005). Their humanhomologues may be attractive targets for pharmacological target-ing in PTSD.

In summary, serotonin, dopamine, and neuroplasticity-relatedgenes are among those that explain variance in fear conditioningand extinction, and are also related to PTSD. Research in animalmodels using genome-wide approaches may provide future genetargets in PTSD and other anxiety disorders (Sokolowska &Hovatta, 2013). Interestingly, one-third of the variance in thevulnerability to anxiety disorders and one-third of the variancein human fear conditioning can be attributed to genetics(Lonsdorf & Kalisch, 2011). This raises the possibility thatabnormalities in fear conditioning and extinction may be a generalvulnerability factor across multiple anxiety disorders.

6. Extinction in other anxiety disorders

The National Institute of Mental Health (NIMH) recently issueda strategic plan that calls for research using dimensions of observa-ble behavior and neurobiological measures to characterize mentaldisorders (Research Domain Criteria [RDoC]; Insel et al., 2010;Morris & Cuthbert, 2012). This strategic plan emphasizes examin-ing a single domain (such as fear conditioning/extinction) at multi-ple levels (from genes to brain function to observable behavior)that cuts across traditional disorder categories. Consistent withthis strategic plan, researchers have begun to examine fear condi-tioning and extinction measures across diagnostic categories (e.g.,Holt et al., 2009; Lissek et al., 2005). Here, we focus on studies ofanxiety disorders other than PTSD. In general, these studies haveincluded psychophysiological (e.g., SCR, EMG) and self-reportmeasures and have generally shown resistance to extinction inanxiety disorders. For example, in the first study of conditioningin psychopathology, Pitman and Orr (1986) examined SCRs during



differential conditioning and extinction in a mixed anxiety disor-der cohort, consisting mostly of individuals with generalized anx-iety, panic disorder, and social phobia. During the extinctionphase, anxiety disorder patients (for whom an angry facial expres-sion had been the CS+) exhibited larger SCRs to the CS+ versus CS�,whereas the control group did not show this difference. This sug-gests that conditioned fear responses are resistant to extinctionin anxiety disorders, although this study alone could not shed lighton potential differences between the anxiety disorders.

Focusing on social phobia, Hermann, Ziegler, Birbaumer, andFlor (2002) studied self-report and psychophysiological correlatesof conditioning and extinction in men with generalized social pho-bia and healthy men. Unlike more typical Pavlovian conditioningstudies, the CSs in this study were neutral facial expressions andthe US was an aversive odor. The social phobia group did not differfrom the healthy comparison group on measures of differential(CS+ vs. CS�) conditioning, although they did show a US expec-tancy bias (i.e., they expected both the CS+ and CS� to be followedby the US). In addition, although the control group showed a de-cline in differential skin conductance responses during extinction,the social phobia group maintained their differential SCR through-out extinction. In other words, the generalized social phobia groupwas more resistant to extinction in terms of SCR. Whether groupswith more circumscribed social phobia (e.g., performance-onlysubtype) would show similar abnormalities is not clear. An fMRIstudy of social phobia revealed no significant between-group brainactivation effects during extinction (Schneider et al., 1999); how-ever, SCR was not measured in that study.

Resistance to extinction has also been reported in panic disor-der. In a more typical paradigm involving neutral photographs asthe CSs and shock as the US, Michael, Blechert, Vriends, Margraf,and Wilhelm (2007) studied differential fear conditioning in pa-tients with panic disorder and healthy control participants. Thetwo groups did not differ on conditioned responses during acquisi-tion. However, during extinction, the panic disorder group exhib-ited larger SCRs to the CS+ and evaluated the CS+ morenegatively than the control group. In contrast, using a simple con-ditioning procedure, Del-Ben et al. (2001) failed to find extinctionabnormalities in individuals with panic disorder.

The results of one study suggest that resistance to extinctioncan also occur in children with anxiety disorders. Liberman, Lipp,Spence, and March (2006) included such children (with social pho-bia, generalized anxiety disorder, separation anxiety, or specificphobia) and non-anxious children in a conditioning paradigminvolving picture CSs and a loud tone US (Liberman et al., 2006).In contrast to the non-anxious children, the anxious children ratedthe CS+ as more fear provoking than the CS� after extinction. Inaddition, startle blink magnitude during the extinction phase waslarger for the CS+ versus CS� in anxious children, but not in non-anxious children.

Most previous studies of extinction in anxiety disorders havefocused on extinction learning rather than on the recall of extinc-tion memories. In a study of the latter type, Milad et al. (2013) useda validated Pavlovian fear conditioning and extinction paradigm(described in Section 3.2) to examine individuals with obsessive–compulsive disorder (OCD) and healthy controls. Functional MRIand SCR data were gathered during conditioning and extinction(on day 1) and during extinction recall (on day 2). Although theOCD and healthy control group exhibited a similar degree of condi-tioning and extinction learning, as determined by SCR measures,the OCD group had lower extinction recall index scores than thecontrol group. In other words, the OCD group had more difficultyrecalling extinction training compared to the healthy controlgroup. In addition, during extinction recall, activation in thevmPFC, posterior cingulate cortex, cerebellum, and putamen waslower in the OCD vs. control group. Furthermore, vmPFC activation


during extinction training was also lower in OCD. Contrary to pre-diction, within the OCD group, OCD symptom severity scores werepositively correlated with vmPFC, cerebellum, and posterior cingu-late activation during extinction recall. OCD symptom severityscores were negatively correlated with activations in the dACCand insular cortex in this same condition. Although OCD appearsto share some extinction abnormalities with PTSD (e.g., impair-ment in extinction recall and diminished activation in vmPFCduring extinction recall), OCD is also marked by other abnormali-ties that were not observed in PTSD (e.g., less activation in the pos-terior cingulate cortex during extinction recall). The unexpectedrelationship between OCD symptom severity and activation duringextinction recall may indicate the presence of other factors thatcontribute to extinction abnormalities in OCD.

The findings above are generally consistent with the idea thatconditioned fear is resistant to extinction (during extinction learn-ing and when tested after a delay) in anxiety disorders. Futurestudies of extinction should directly compare different anxietydisorder groups within the same study. Minimal extinction differ-ences between specific anxiety disorder groups could potentiallysuggest that they lie on the same underlying continuum and mayhave a common pathophysiology. Thus far, few studies have exam-ined the neural correlates of extinction impairment across anxietydisorders. Nevertheless, the psychophysiological evidence of im-paired extinction in anxiety disorders might suggest similar func-tional abnormalities in the amygdala, dACC, vmPFC, andhippocampus among these disorders. Indeed, neuroimaging stud-ies involving other paradigms have revealed functional abnormal-ities in these very structures across anxiety disorders, although thedirection of the vmPFC abnormality appears to differ betweenPTSD and other anxiety disorders (e.g., Etkin & Wager, 2007) andthe pathophysiology of OCD appears to involve thalamo-cortico-striatal circuits as well (Shin & Liberzon, 2010). Additional neuro-imaging studies of extinction across anxiety disorders are neededto confirm speculations of shared pathophysiology.

6.1. Drug and neuromodulation treatments for PTSD and other anxietydisorders

As we described earlier, extinction involves repeatedly present-ing the CS+ (e.g., tone) without the US (e.g., shock) such that theindividual learns that the CS+ no longer predicts the US, and theCR (e.g., freezing in rodents or SCR in humans) diminishes. Re-peated exposure to trauma-related cues lies at the heart of expo-sure therapy and related cognitive-behavioral techniques, whichare the most well accepted treatments for PTSD and other anxietydisorders (e.g., Hofmann, Sawyer, Korte, & Smits, 2009; Hofmann &Smits, 2008).

Studies involving the pharmacologic manipulation of extinctionin rodents and in healthy humans have helped identify new treat-ment options for individuals with anxiety disorders. D-cycloserine(DCS) is one of the most fruitful examples of this (Davis, 2011; Hof-mann, Wu, & Boettcher, 2013). DCS is an antibiotic that also acts asa partial agonist at the glycine site of the NMDA glutamate recep-tor and has been shown to facilitate extinction learning in rodents(Davis, Ressler, Rothbaum, & Richardson, 2006; Norberg, Krystal, &Tolin, 2008). In clinical studies, DCS is typically administered priorto exposure sessions and has been found to facilitate symptomaticimprovement in phobia (e.g., Ressler et al., 2004), OCD (e.g.,Chasson et al., 2010; Wilhelm et al., 2008), social anxiety disorder(Hofmann, Smits, et al., 2013), and panic disorder (Otto et al.,2010), although it may be less effective in PTSD (de Kleine,Hendriks, Kusters, Broekman, & van Minnen, 2012; Litz et al.,2012). DCS appears to be most effective in treatment sessions dur-ing which there is within-session decline in fear (Hofmann, Wu,et al., 2013; Smits et al., 2013), and perhaps smaller such declines



could explain the relatively lackluster findings in PTSD thus far.Although recent studies have suggested that DCS may expediteimprovement, rather than improve overall outcome (Chassonet al., 2010; Hofmann, Smits, et al., 2013; Norberg et al., 2008),DCS could still be clinically useful by providing faster symptom re-lief, decreasing the risk of early termination of treatment, anddecreasing the cost of care.

Other agents have been shown to improve extinction and maythus prove helpful in the treatment of anxiety disorders. Some arealready widely utilized in the treatment of anxiety disorders (e.g.,serotonin reuptake inhibitors; SRIs) and others are not (e.g., gluco-corticoids, cannabinoids). With regard to SRIs, when administeredbefore extinction training in rats, venlafaxine facilitated between-session extinction (Yang et al., 2012). In addition, chronicadministration (21 days) of venlafaxine prevented reinstatementof conditioned fear (Yang et al., 2012). When administered afterextinction in rats, fluoxetine prevented stress-induced reinstate-ment of conditioned fear (Deschaux et al., 2013). When combinedwith extinction training in mice, fluoxetine facilitated extinction(Karpova et al., 2011; but see also Burghardt, Sigurdsson, Gorman,McEwen, & LeDoux, 2013, which suggests that chronic treatmentwith citalopram before extinction training impairs extinction inrats). Recently, researchers have investigated whether pre-treat-ment with a SRI before conditioning/extinction training can facili-tate extinction in healthy humans. In a randomized, placebo-controlled trial, Bui et al. (2013) pre-treated 18 participants withescitalopram (10 mg/day) and 20 participants with placebo for14 days. At the end of this treatment period, participants underwentPavlovian fear conditioning and extinction procedures. Althoughthe two groups did not differ on fear conditioning measures, theescitalopram group exhibited greater extinction (as measured bySCR), compared to the placebo group. If replicated, this findingwould appear to support the potential role of SRIs in the preventionof PTSD. The notion that SRIs may expedite extinction learning isconsistent with recent research suggesting that combining SRIs withcognitive-behavioral therapy may be beneficial (Schneier et al.,2012).

Glucocorticoids, which include stress hormones released fromthe adrenal cortex, have also been shown to affect extinction in ro-dents and symptom severity in anxiety disorders. For example, thesynthetic glucocorticoid dexamethasone administered prior to orafter extinction training enhanced extinction in rats (Yang, Chao,& Lu, 2006). In a randomized, double-blind, placebo-controlledstudy of specific phobia for heights, cortisol administered 1 h be-fore virtual-reality based exposure therapy significantly reducedfear at post-treatment and at a 1-month follow-up (de Quervainet al., 2011). There is also some evidence for hydrocortisone aug-mentation of exposure therapy in PTSD (Surís, North, Adinoff, Pow-ell, & Greene, 2010; Yehuda & LeDoux, 2007) and low-dose cortisoltreatment of PTSD symptoms (Aerni et al., 2004).

Other agents have been shown to improve extinction measures.For example, cannabinoid agonists increased extinction in rodents(Chhatwal, Davis, Maguschak, & Ressler, 2005; Chhatwal & Ressler,2007), and in healthy humans (Das et al., 2013; Rabinak et al.,2013). Intranasal oxytocin also appears to increase extinction inhealthy humans (Acheson et al., 2013).

Another way to manipulate extinction would be to stimulatethe brain regions critically involved in extinction and extinction re-call. Previous research in rodents has suggested that direct electri-cal stimulation of the infralimbic cortex in the presence of the CS+or fear-conditioned context reduces conditioned freezing (Milad &Quirk, 2002; Milad, Vidal-Gonzalez, & Quirk, 2004; Thompsonet al., 2010). Baek, Chae, and Jeong (2012) reported similar findingswith transcranial magnetic stimulation (TMS; positioned 3 mmanterior to bregma) in rats. In an intriguing new study in humans,Isserles et al. (2013) administered deep TMS of the frontal cortex


while subjects with PTSD were engaged in traumatic memory re-call. The PTSD subjects who received TMS during traumatic mem-ory recall showed reductions in intrusive memories and heart rateresponses to the traumatic recall, whereas comparison groups didnot. An earlier study (Osuch et al., 2009) reported similar findings,although the location and intensity of TMS stimulation wasdifferent from that of Isserles et al. (2013). Manipulating arousalcircuitry by vagus nerve stimulation increases extinction learningin rats (Peña, Engineer, & McIntyre, 2013), and may be a promisingadjunct to exposure-based therapy in PTSD.

As mentioned earlier, blocking the reconsolidation of the fearmemory at retrieval is a new focus of possible treatment for PTSD.Basic research suggests that reconsolidation blockade could beachieved by administering either pharmacologic agents (e.g.,Diergaarde, Schoffelmeer, & De Vries, 2008; Gamache et al.,2012; Nader et al., 2000; Pitman et al., 2011) or extinction training(e.g., Monfils et al., 2009) immediately after memory reactivation(within the lability window). In line with the first method of block-ing reconsolidation, Brunet et al. (2008) asked participants withPTSD to provide detailed descriptions (called ‘‘scripts’’) of theirtraumatic events (thereby reactivating their traumatic memories)and then administered either propranolol or placebo in a random-ized, double-blind design. One week later, participants’ psycho-physiological responses to their own trauma scripts weremeasured. The group who received post-reactivation propranololhad smaller heart rate and SCR responses to the trauma scriptsas compared to the placebo group. Although the study lacked acomparison group of PTSD patients who received propranolol inthe absence of memory reactivation, these initial results areencouraging and warrant further examination.

Consistent with the second possible method of blocking recon-solidation, Rothbaum et al. (2012) studied the effects of administer-ing a modified version of prolonged exposure therapy immediately(within an average of approximately 12 h) post-trauma in an emer-gency department setting. Compared to an assessment-only controlgroup, patients who received this intervention had fewer PTSD anddepressive symptoms at 4 and 12 weeks post-trauma. It should benoted that previous attempts to initiate treatment immediatelyafter trauma have not been successful (e.g., Kearns, Ressler, Zatzick,& Rothbaum, 2012; Mayou, Ehlers, & Hobbs, 2000), most likely dueto the different type of treatment implemented (psychologicaldebriefing vs. prolonged exposure) and/or later treatment initiation(in many cases, two or more days post trauma, which is most likelyoutside of the memory lability window).

7. Conclusion

In summary, fear conditioning and extinction has been a fruitfulparadigm for understanding PTSD and other anxiety disorders.Rodent and healthy human studies have demonstrated that fearconditioning involves the amygdala and dACC creating a CS–USassociation. Fear extinction involves the vmPFC and hippocampusinteracting to form a context-dependent CS–noUS association. Ge-netic studies have explained some of the variance in conditioningand extinction in healthy individuals, and may yield insights intothe genetic basis of PTSD. Furthermore, fear conditioning andextinction abnormalities may be a behavioral biomarker forgeneral vulnerability to anxiety disorders, raising the intriguingpossibility that interventions that enhance extinction learningcould have beneficial effects for these disorders.

Acknowledgments

The authors are supported in part by NIMH 5R01MH054636.MBV is supported by a National Defense Science and EngineeringGraduate Fellowship (NDSEG).



References

Acheson, D., Feifel, D., de Wilde, S., McKinney, R., Lohr, J., & Risbrough, V. (2013). Theeffect of intranasal oxytocin treatment on conditioned fear extinction and recallin a healthy human sample. Psychopharmacology, 229(1), 199–208.

Aerni, A., Traber, R., Hock, C., Roozendaal, B., Schelling, G., Papassotiropoulos, A.,et al. (2004). Low-dose cortisol for symptoms of posttraumatic stress disorder.The American Journal of Psychiatry, 161(8), 1488–1490.

Alvarez, R. P., Biggs, A., Chen, G., Pine, D. S., & Grillon, C. (2008). Contextual fearconditioning in humans: Cortical–hippocampal and amygdala contributions.The Journal of Neuroscience, 28(24), 6211–6219.

Amano, T., Unal, C. T., & Paré, D. (2010). Synaptic correlates of fear extinction in theamygdala. Nature Neuroscience, 13(4), 489–494.

Amstadter, A., Nugent, N., & Koenen, K. (2009). Genetics of PTSD: Fear conditioningas a model for future research. Psychiatric Annals, 39(6), 358–367.

American Psychological Association (2000). Diagnostic and statistical manual ofmental disorders (4th ed.). APA Press.

Astur, R. S., St Germain, S. A., Tolin, D., Ford, J., Russell, D., et al. (2006). Hippocampusfunction predicts severity of post-traumatic stress disorder. CyberPsychology &Behavior, 9(2), 234–240.

Baek, K., Chae, J. H., & Jeong, J. (2012). The effect of repetitive transcranial magneticstimulation on fear extinction in rats. Neuroscience, 200, 159–165.

Barrett, J., & Armony, J. L. (2009). Influence of trait anxiety on brain activity duringthe acquisition and extinction of aversive conditioning. Psychological Medicine,39(2), 255–265.

Berretta, S., Pantazopoulos, H., Caldera, M., Pantazopoulos, P., & Paré, D. (2005).Infralimbic cortex activation increases c-Fos expression in intercalated neuronsof the amygdala. Neuroscience, 132(4), 943–953.

Bettencourt, K. C., & Somers, D. C. (2009). Effects of target enhancement anddistractor suppression on multiple object tracking capacity. Journal of Vision,9(7), 9.

Blair, H. T., Schafe, G. E., Bauer, E. P., Rodrigues, S. M., & LeDoux, J. E. (2001). Synapticplasticity in the lateral amygdala: A cellular hypothesis of fear conditioning.Learning & Memory, 8(5), 229–242.

Blechert, J., Michael, T., Vriends, N., Margraf, J., & Wilhelm, F. H. (2007). Fearconditioning in posttraumatic stress disorder: Evidence for delayed extinctionof autonomic, experiential, and behavioural responses. Behaviour Research andTherapy, 45(9), 2019–2033.

Bouton, M. E. (2004). Context and behavioral processes in extinction. Learning &Memory, 11(5), 485–494.

Bouton, M. E., García-Gutiérrez, A., Zilski, J., & Moody, E. W. (2006). Extinction inmultiple contexts does not necessarily make extinction less vulnerable torelapse. Behaviour Research and Therapy, 44(7), 983–994.

Bouton, M. E., Westbrook, R. F., Corcoran, K. A., & Maren, S. (2006). Contextual andtemporal modulation of extinction: Behavioral and biological mechanisms.Biological Psychiatry, 60(4), 352–360.

Bremner, J. D., Narayan, M., Staib, L. H., Southwick, S. M., McGlashan, T., & Charney,D. S. (1999). Neural correlates of memories of childhood sexual abuse in womenwith and without posttraumatic stress disorder. The American Journal ofPsychiatry, 156(11), 1787–1795.

Bremner, J. D., Vermetten, E., Schmahl, C., Vaccarino, V., Vythilingam, M., Afzal, N.,et al. (2005). Positron emission tomographic imaging of neural correlates of afear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychological Medicine, 35(6),791–806.

Bremner, J. D., Vythilingam, M., Vermetten, E., Southwick, S. M., McGlashan, T.,Staib, L. H., et al. (2003). Neural correlates of declarative memory foremotionally valenced words in women with posttraumatic stress disorderrelated to early childhood sexual abuse. Biological Psychiatry, 53(10),879–889.

Brewin, C. R. (2011). The nature and significance of memory disturbance inposttraumatic stress disorder. Annual Review of Clinical Psychology, 7, 203–227.

Brohawn, K. H., Offringa, R., Pfaff, D. L., Hughes, K. C., & Shin, L. M. (2010). The neuralcorrelates of emotional memory in posttraumatic stress disorder. BiologicalPsychiatry, 68(11), 1023–1030.

Brunet, A., Orr, S. P., Tremblay, J., Robertson, K., Nader, K., & Pitman, R. K. (2008).Effect of post-retrieval propranolol on psychophysiologic responding duringsubsequent script-driven traumatic imagery in post-traumatic stress disorder.Journal of Psychiatric Research, 42(6), 503–506.

Bryant, R. A., Felmingham, K. L., Falconer, E. M., Pe Benito, L., Dobson-Stone, C.,Pierce, K. D., et al. (2010). Preliminary evidence of the short allele of theserotonin transporter gene predicting poor response to cognitive behaviortherapy in posttraumatic stress disorder. Biological Psychiatry, 67(12),1217–1219.

Bryant, R. A., Felmingham, K. L., Kemp, A. H., Barton, M., Peduto, A. S., Rennie, C.,et al. (2005). Neural networks of information processing in posttraumatic stressdisorder: A functional magnetic resonance imaging study. Biological Psychiatry,58(2), 111–118.

Bryant, R. A., O’Donnell, M. L., Creamer, M., McFarlane, A. C., & Silove, D. (2013). Amultisite analysis of the fluctuating course of posttraumatic stress disorder.JAMA Psychiatry, 70(8), 839–846.

Buchel, C., Dolan, R. J., Armony, J. L., & Friston, K. J. (1999). Amygdala-hippocampalinvolvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging. The Journal of Neuroscience,19(24), 10869–10876.


Buchel, C., Morris, J., Dolan, R. J., & Friston, K. J. (1998). Brain systems mediatingaversive conditioning: An event-related fMRI study. Neuron, 20(5), 947–957.

Bui, E., Orr, S. P., Jacoby, R. J., Keshaviah, A., LeBlanc, N. J., Milad, M. R., et al. (2013).Two weeks of pretreatment with escitalopram facilitates extinction learning inhealthy individuals. Human Psychopharmacology, 28(5), 447–456.

Burghardt, N. S., Sigurdsson, T., Gorman, J. M., McEwen, B. S., & LeDoux, J. E. (2013).Chronic antidepressant treatment impairs the acquisition of fear extinction.Biological Psychiatry, 73(11), 1078–1086.

Burgos-Robles, A., Vidal-Gonzalez, I., & Quirk, G. J. (2009). Sustained conditionedresponses in prelimbic prefrontal neurons are correlated with fear expressionand extinction failure. The Journal of Neuroscience, 29(26), 8474–8482.

Campeau, S., & Davis, M. (1995). Involvement of subcortical and cortical afferents tothe lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visualconditioned stimuli. The Journal of Neuroscience, 15(3), 2312–2327.

Chasson, G. S., Buhlmann, U., Tolin, D. F., Rao, S. R., Reese, H. E., Rowley, T., et al.(2010). Need for speed: Evaluating slopes of OCD recovery in behavior therapyenhanced with D-cycloserine. Behaviour Research and Therapy, 48(7), 675–679.

Cheng, D. T., Knight, D. C., Smith, C. N., & Helmstetter, F. J. (2006). Human amygdalaactivity during the expression of fear responses. Behavioral Neuroscience, 120(6),1187–1195.

Cheng, D. T., Knight, D. C., Smith, C. N., Stein, E. A., & Helmstetter, F. J. (2003).Functional MRI of human amygdala activity during Pavlovian fear conditioning:Stimulus processing versus response expression. Behavioral Neuroscience,117(1), 3–10.

Cheng, D. T., Richards, J., & Helmstetter, F. J. (2007). Activity in the human amygdalacorresponds to early, rather than late period autonomic responses to a signal forshock. Learning & Memory, 14(7), 485–490.

Chhatwal, J. P., Davis, M., Maguschak, K. A., & Ressler, K. J. (2005). Enhancingcannabinoid neurotransmission augments the extinction of conditioned fear.Neuropsychopharmacology, 30(3), 516–524.

Chhatwal, J. P., & Ressler, K. J. (2007). Modulation of fear and anxiety by theendogenous cannabinoid system. CNS Spectrums, 12(3), 211–220.

Cornelis, M. C., Nugent, N. R., Amstadter, A. B., & Koenen, K. C. (2010). Genetics ofpost-traumatic stress disorder: Review and recommendations for genome-wideassociation studies. Current Psychiatry Reports, 12(4), 313–326.

Cris�an, L. G., Pana, S., Vulturar, R., Heilman, R. M., Szekely, R., Druga, B., et al. (2009).Genetic contributions of the serotonin transporter to social learning of fear andeconomic decision making. Social Cognitive and Affective Neuroscience, 4(4),399–408.

Cohen, D. H., & Randall, D. C. (1984). Classical conditioning of cardiovascularresponses. Annual Review of Physiology, 46, 187–197.

Critchley, H. D., Mathias, C. J., & Dolan, R. J. (2002). Fear conditioning in humans: Theinfluence of awareness and autonomic arousal on functional neuroanatomy.Neuron, 33(4), 653–663.

Cukor, J., Spitalnick, J., Difede, J., Rizzo, A., & Rothbaum, B. O. (2009). Emergingtreatments for PTSD. Clinical Psychology Review, 29(8), 715–726.

Das, R. K., Kamboj, S. K., Ramadas, M., Yogan, K., Gupta, V., Redman, E., et al. (2013).Cannabidiol enhances consolidation of explicit fear extinction in humans.Psychopharmacology, 226(4), 781–792.

Davis, M. (2001). Fear-potentiated startle in rats. In Jacqueline N. Crawley et al.(Eds.), Current protocols in neuroscience. Unit 8.11A (Editorial Board).

Davis, M. (2011). NMDA receptors and fear extinction: Implications for cognitivebehavioral therapy. Dialogues in Clinical Neuroscience, 13(4), 463–474.

Davis, M., Ressler, K., Rothbaum, B. O., & Richardson, R. (2006). Effects of D-cycloserine on extinction: Translation from preclinical to clinical work.Biological Psychiatry, 60(4), 369–375.

Davis, M., Walker, D. L., Miles, L., & Grillon, C. (2010). Phasic vs. sustained fear in ratsand humans: Role of the extended amygdala in fear vs. anxiety.Neuropsychopharmacology, 35(1), 105–135.

Davis, M., & Whalen, P. J. (2001). The amygdala: Vigilance and emotion. MolecularPsychiatry, 6(1), 13–34.

de Kleine, R. A., Hendriks, G.-J., Kusters, W. J. C., Broekman, T. G., & van Minnen, A.(2012). A randomized placebo-controlled trial of D-cycloserine to enhanceexposure therapy for posttraumatic stress disorder. Biological Psychiatry, 71(11),962–968.

de Quervain, D. J.-F., Bentz, D., Michael, T., Bolt, O. C., Wiederhold, B. K., Margraf, J.,et al. (2011). Glucocorticoids enhance extinction-based psychotherapy.Proceedings of the National Academy of Sciences of the United States of America,108(16), 6621–6625.

de Vries, G.-J., & Olff, M. (2009). The lifetime prevalence of traumatic events andposttraumatic stress disorder in the Netherlands. Journal of Traumatic Stress,22(4), 259–267.

Del-Ben, C. M., Vilela, J. A., Hetem, L. A., Guimarães, F. S., Graeff, F. G., & Zuardi, A. W.(2001). Do panic patients process unconditioned fear vs. conditioned anxietydifferently than normal subjects? Psychiatry Research, 104(3), 227–237.

Deschaux, O., Zheng, X., Lavigne, J., Nachon, O., Cleren, C., Moreau, J.-L., et al. (2013).Post-extinction fluoxetine treatment prevents stress-induced reemergence ofextinguished fear. Psychopharmacology, 225(1), 209–216.

Diergaarde, L., Schoffelmeer, A. N. M., & De Vries, T. J. (2008). Pharmacologicalmanipulation of memory reconsolidation: Towards a novel treatment ofpathogenic memories. European Journal of Pharmacology, 585(2–3), 453–457.

Difede, J., Cukor, J., Jayasinghe, N., Patt, I., Jedel, S., Spielman, L., et al. (2007). Virtualreality exposure therapy for the treatment of posttraumatic stress disorderfollowing September 11, 2001. The Journal of Clinical Psychiatry, 68(11),1639–1647.



Digangi, J., Guffanti, G., McLaughlin, K. A., & Koenen, K. C. (2013). Consideringtrauma exposure in the context of genetics studies of posttraumatic stressdisorder: A systematic review. Biology of Mood & Anxiety Disorders, 3(1), 2.

Dohrenwend, B. P., Turner, J. B., Turse, N. A., Adams, B. G., Koenen, K. C., & Marshall,R. (2006). The psychological risks of Vietnam for U.S. veterans: A revisit withnew data and methods. Science, 313(5789), 979–982.

Doronbekov, T. K., Tokunaga, H., Ikejiri, Y., Kazui, H., Hatta, N., Masaki, Y., et al.(2005). Neural basis of fear conditioning induced by video clip: Positronemission tomography study. Psychiatry and Clinical Neurosciences, 59(2),155–162.

Elzinga, B. M., & Bremner, J. D. (2002). Are the neural substrates of memory the finalcommon pathway in posttraumatic stress disorder (PTSD)? Journal of AffectiveDisorders, 70(1), 1–17.

Etkin, A., & Wager, T. D. (2007). Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specificphobia. The American Journal of Psychiatry, 164(10), 1476–1488.

Eysenck, H. J. (1979). The conditioning model of neurosis. The Behavioral and BrainSciences, 2, 155–199.

Fani, N., Tone, E. B., Phifer, J., Norrholm, S. D., Bradley, B., Ressler, K. J., et al. (2012).Attention bias toward threat is associated with exaggerated fear expression andimpaired extinction in PTSD. Psychological Medicine, 42(3), 533–543.

Fonzo, G. A., Flagan, T. M., Sullivan, S., Allard, C. B., Grimes, E. M., Simmons, A. N.,et al. (2013). Neural functional and structural correlates of childhoodmaltreatment in women with intimate-partner violence-relatedposttraumatic stress disorder. Psychiatry Research: Neuroimaging, 211(2),93–103.

Frielingsdorf, H., Bath, K. G., Soliman, F., Difede, J., Casey, B. J., & Lee, F. S. (2010).Variant brain-derived neurotrophic factor Val66Met endophenotypes:Implications for posttraumatic stress disorder. Annals of the New YorkAcademy of Sciences, 1208, 150–157.

Frueh, B. C., Grubaugh, A. L., Yeager, D. E., & Magruder, K. M. (2009). Delayed-onsetpost-traumatic stress disorder among war veterans in primary care clinics. TheBritish Journal of Psychiatry: The Journal of Mental Science, 194(6), 515–520.

Furmark, T., Fischer, H., Wik, G., Larsson, M., & Fredrikson, M. (1997). The amygdalaand individual differences in human fear conditioning. NeuroReport, 8(18),3957–3960.

Gamache, K., Pitman, R. K., & Nader, K. (2012). Preclinical evaluation ofreconsolidation blockade by clonidine as a potential novel treatment forposttraumatic stress disorder. Neuropsychopharmacology, 37(13), 2789–2796.

Garpenstrand, H., Annas, P., Ekblom, J., Oreland, L., & Fredrikson, M. (2001). Humanfear conditioning is related to dopaminergic and serotonergic biologicalmarkers. Behavioral Neuroscience, 115(2), 358–364.

Gerardi, M., Rothbaum, B. O., Ressler, K., Heekin, M., & Rizzo, A. (2008). Virtualreality exposure therapy using a virtual Iraq: Case report. Journal of TraumaticStress, 21(2), 209–213.

Gilbertson, M. W., Shenton, M. E., Ciszewski, A., Kasai, K., Lasko, N. B., Orr, S. P., et al.(2002). Smaller hippocampal volume predicts pathologic vulnerability topsychological trauma. Nature Neuroscience, 5(11), 1242–1247.

Glotzbach-Schoon, E., Andreatta, M., Reif, A., Ewald, H., Tröger, C., Baumann, C., et al.(2013). Contextual fear conditioning in virtual reality is affected by 5HTTLPRand NPSR1 polymorphisms: Effects on fear-potentiated startle. Frontiers inBehavioral Neuroscience, 7, 31.

Glover, E. M., Phifer, J. E., Crain, D. F., Norrholm, S. D., Davis, M., Bradley, B., et al.(2011). Tools for translational neuroscience: PTSD is associated withheightened fear responses using acoustic startle but not skin conductancemeasures. Depression and Anxiety, 28(12), 1058–1066.

Goenjian, A. K., Bailey, J. N., Walling, D. P., Steinberg, A. M., Schmidt, D., Dandekar,U., et al. (2012). Association of TPH1, TPH2, and 5HTTLPR with PTSD anddepressive symptoms. Journal of Affective Disorders, 140(3), 244–252.

Gottfried, J. A., & Dolan, R. J. (2004). Human orbitofrontal cortex mediates extinctionlearning while accessing conditioned representations of value. NatureNeuroscience, 7(10), 1144–1152.

Grillon, C., & Baas, J. (2003). A review of the modulation of the startle reflex byaffective states and its application in psychiatry. Clinical Neurophysiology,114(9), 1557–1579.

Grillon, C., & Morgan, C. A. (1999). Fear-potentiated startle conditioning to explicitand contextual cues in Gulf War veterans with posttraumatic stress disorder.Journal of Abnormal Psychology, 108(1), 134–142.

Grillon, C., Morgan, C. A., Davis, M., & Southwick, S. M. (1998). Effects ofexperimental context and explicit threat cues on acoustic startle in Vietnamveterans with posttraumatic stress disorder. Biological Psychiatry, 44(10),1027–1036.

Grupe, D. W., Oathes, D. J., & Nitschke, J. B. (2013). Dissecting the anticipation ofaversion reveals dissociable neural networks. Cerebral Cortex, 23(8), 1874–1883.

Guthrie, R. M., & Bryant, R. A. (2006). Extinction learning before trauma andsubsequent posttraumatic stress. Psychosomatic Medicine, 68(2), 307–311.

Hajcak, G., Castille, C., Olvet, D. M., Dunning, J. P., Roohi, J., & Hatchwell, E. (2009).Genetic variation in brain-derived neurotrophic factor and human fearconditioning. Genes, Brain, and Behavior, 8(1), 80–85.

Hamm, A. O., Greenwald, M. K., Bradley, M. M., & Lang, P. J. (1993). Emotionallearning, hedonic change, and the startle probe. Journal of Abnormal Psychology,102(3), 453–465.

Hamm, A. O., & Vaitl, D. (1996). Affective learning: Awareness and aversion.Psychophysiology, 33(6), 698–710.

Harris, B. (2011). Letting go of little Albert: Disciplinary memory, history, and theuses of myth. Journal of the History of the Behavioral Sciences, 47, 1–17.


Hayes, J. P., LaBar, K. S., McCarthy, G., Selgrade, E., Nasser, J., Dolcos, F., et al. (2011).Reduced hippocampal and amygdala activity predicts memory distortions fortrauma reminders in combat-related PTSD. Journal of Psychiatric Research, 45(5),660–669.

Hayes, J. P., LaBar, K. S., Petty, C. M., McCarthy, G., & Morey, R. A. (2009). Alterationsin the neural circuitry for emotion and attention associated with posttraumaticstress symptomatology. Psychiatry Research, 172(1), 7–15.

Hayes, J. P., VanElzakker, M. B., & Shin, L. M. (2012). Emotion and cognitioninteractions in PTSD: A review of neurocognitive and neuroimaging studies.Frontiers in Integrative Neuroscience, 6, 1–14.

Heeger, D. J., & Ress, D. (2002). What does fMRI tell us about neuronal activity?Nature Reviews Neuroscience, 3(2), 142–151.

Hermann, A., Küpper, Y., Schmitz, A., Walter, B., Vaitl, D., Hennig, J., et al. (2012).Functional gene polymorphisms in the serotonin system and traumatic lifeevents modulate the neural basis of fear acquisition and extinction. PLoS ONE,7(9), e44352.

Hermann, C., Ziegler, S., Birbaumer, N., & Flor, H. (2002). Psychophysiological andsubjective indicators of aversive Pavlovian conditioning in generalized socialphobia. Biological Psychiatry, 52(4), 328–337.

Herry, C., Ciocchi, S., Senn, V., Demmou, L., Müller, C., & Lüthi, A. (2008). Switchingon and off fear by distinct neuronal circuits. Nature, 454(7204), 600–606.

Herry, C., Ferraguti, F., Singewald, N., Letzkus, J. J., Ehrlich, I., & Lüthi, A. (2010).Neuronal circuits of fear extinction. The European Journal of Neuroscience, 31(4),599–612.

Hettema, J. M., Annas, P., Neale, M. C., Kendler, K. S., & Fredrikson, M. (2003). A twinstudy of the genetics of fear conditioning. Archives of General Psychiatry, 60(7),702–708.

Hofmann, S. G., Sawyer, A. T., Korte, K. J., & Smits, J. A. J. (2009). Is it beneficial to addpharmacotherapy to cognitive-behavioral therapy when treating anxietydisorders? A meta-analytic review. International Journal of Cognitive Therapy,2(2), 160–175.

Hofmann, S. G., & Smits, J. A. J. (2008). Cognitive-behavioral therapy for adultanxiety disorders: A meta-analysis of randomized placebo-controlled trials. TheJournal of Clinical Psychiatry, 69(4), 621–632.

Hofmann, S. G., Smits, J. A. J., Rosenfield, D., Simon, N., Otto, M. W., Meuret, A. E.,et al. (2013). D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder. The American Journal ofPsychiatry, 170(7), 751–758.

Hofmann, S. G., Wu, J. Q., & Boettcher, H. (2013). D-Cycloserine as an augmentationstrategy for cognitive behavioral therapy of anxiety disorders. Biology of Mood &Anxiety Disorders, 3(1), 11.

Holmes, A., & Singewald, N. (2013). Individual differences in recovery fromtraumatic fear. Trends in Neurosciences, 36(1), 23–31.

Holt, D. J., Lebron-Milad, K., Milad, M. R., Rauch, S. L., Pitman, R. K., Orr, S. P., et al.(2009). Extinction memory is impaired in schizophrenia. Biological Psychiatry,65(6), 455–463.

Huertas, E., Ponce, G., Koeneke, M. A., Poch, C., España-Serrano, L., Palomo, T.,et al. (2010). The D2 dopamine receptor gene variant C957T affects humanfear conditioning and aversive priming. Genes, Brain, and Behavior, 9(1),103–109.

Hughes, K. C., & Shin, L. M. (2011). Functional neuroimaging studies of post-traumatic stress disorder. Expert Review of Neurotherapeutics, 11(2), 275–285.

Inda, M. C., Muravieva, E. V., & Alberini, C. M. (2011). Memory retrieval and thepassage of time: From reconsolidation and strengthening to extinction. TheJournal of Neuroscience, 31(5), 1635–1643.

Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D. S., Quinn, K., et al. (2010).Research domain criteria (RDoC): Toward a new classification framework forresearch on mental disorders. The American Journal of Psychiatry, 167(7),748–751.

Isserles, M., Shalev, A. Y., Roth, Y., Peri, T., Kutz, I., Zlotnick, E., et al. (2013).Effectiveness of deep transcranial magnetic stimulation combined with a briefexposure procedure in post-traumatic stress disorder – A pilot study. BrainStimulation, 6(3), 377–383.

Javanbakht, A., Liberzon, I., Amirsadri, A., Gjini, K., & Boutros, N. N. (2011). Event-related potential studies of post-traumatic stress disorder: A critical review andsynthesis. Biology of Mood & Anxiety Disorders, 1(1), 5.

Johnson, L. R., McGuire, J., Lazarus, R., & Palmer, A. A. (2012). Pavlovian fear memorycircuits and phenotype models of PTSD. Neuropharmacology, 62(2), 638–646.

Jovanovic, T., Kazama, A., Bachevalier, J., & Davis, M. (2012). Impaired safety signallearning may be a biomarker of PTSD. Neuropharmacology, 62(2), 695–704.

Jovanovic, T., Keyes, M., Fiallos, A., Myers, K. M., Davis, M., & Duncan, E. J. (2005).Fear potentiation and fear inhibition in a human fear-potentiated startleparadigm. Biological Psychiatry, 57(12), 1559–1564.

Jovanovic, T., & Norrholm, S. D. (2011). Neural mechanisms of impaired fearinhibition in posttraumatic stress disorder. Frontiers in Behavioral Neuroscience,5, 44.

Jovanovic, T., Norrholm, S. D., Blanding, N. Q., Davis, M., Duncan, E., Bradley, B., &Ressler, K. J. (2010). Impaired fear inhibition is a biomarker of PTSD but notdepression. Depression and Anxiety, 27(3), 244–251.

Jovanovic, T., Norrholm, S. D., Fennell, J. E., Keyes, M., Fiallos, A. M., Myers, K. M.,et al. (2009). Posttraumatic stress disorder may be associated with impairedfear inhibition: Relation to symptom severity. Psychiatry Research, 167(1–2),151–160.

Jovanovic, T., & Ressler, K. J. (2010). How the neurocircuitry and genetics of fearinhibition may inform our understanding of PTSD. The American Journal ofPsychiatry, 167(6), 648–662.



Kalisch, R., Korenfeld, E., Stephan, K. E., Weiskopf, N., Seymour, B., & Dolan, R. J.(2006). Context-dependent human extinction memory is mediated by aventromedial prefrontal and hippocampal network. The Journal ofNeuroscience, 26(37), 9503–9511.

Karpova, N. N., Pickenhagen, A., Lindholm, J., Tiraboschi, E., Kulesskaya, N.,Agústsdóttir, A., et al. (2011). Fear erasure in mice requires synergybetween antidepressant drugs and extinction training. Science, 334(6063),1731–1734.

Kattoor, J., Gizewski, E. R., Kotsis, V., Benson, S., Gramsch, C., Theysohn, N., et al.(2013). Fear conditioning in an abdominal pain model: Neural responses duringassociative learning and extinction in healthy subjects. PLoS ONE, 8(2), e51149.

Kearns, M. C., Ressler, K. J., Zatzick, D., & Rothbaum, B. O. (2012). Early interventionsfor PTSD: A review. Depression and Anxiety, 29(10), 833–842.

Kim, J. J., & Fanselow, M. S. (1992). Modality-specific retrograde amnesia of fear.Science, 256(5057), 675–677.

Kindt, M., Soeter, M., & Vervliet, B. (2009). Beyond extinction: Erasing human fearresponses and preventing the return of fear. Nature Neuroscience, 12(3),256–258.

Klucken, T., Kagerer, S., Schweckendiek, J., Tabbert, K., Vaitl, D., & Stark, R. (2009).Neural, electrodermal and behavioral response patterns in contingency awareand unaware subjects during a picture–picture conditioning paradigm.Neuroscience, 158(2), 721–731.

Knight, D. C., Nguyen, H. T., & Bandettini, P. A. (2005). The role of the humanamygdala in the production of conditioned fear responses. NeuroImage, 26(4),1193–1200.

Knight, D. C., Smith, C. N., Cheng, D. T., Stein, E. A., & Helmstetter, F. J. (2004).Amygdala and hippocampal activity during acquisition and extinction of humanfear conditioning. Cognitive, Affective & Behavioral Neuroscience, 4(3), 317–325.

Knight, D. C., Waters, N. S., & Bandettini, P. A. (2009). Neural substrates of explicitand implicit fear memory. NeuroImage, 45(1), 208–214.

LaBar, K. S., & Cabeza, R. (2006). Cognitive neuroscience of emotional memory.Nature Reviews Neuroscience, 7(1), 54–64.

LaBar, K. S., Gatenby, J. C., Gore, J. C., LeDoux, J. E., & Phelps, E. A. (1998). Humanamygdala activation during conditioned fear acquisition and extinction: Amixed-trial fMRI study. Neuron, 20(5), 937–945.

Lang, S., Kroll, A., Lipinski, S. J., Wessa, M., Ridder, S., Christmann, C., et al. (2009).Context conditioning and extinction in humans: Differential contribution of thehippocampus, amygdala and prefrontal cortex. The European Journal ofNeuroscience, 29(4), 823–832.

Lanius, R. A., Williamson, P. C., Densmore, M., Boksman, K., Gupta, M. A., Neufeld, R.W., et al. (2001). Neural correlates of traumatic memories in posttraumaticstress disorder: A functional MRI investigation. The American Journal ofPsychiatry, 158(11), 1920–1922.

LeDoux, J. E. (2000). Emotion circuits in the brain. Annual Review of Neuroscience, 23,155–184.

Liberman, L. C., Lipp, O. V., Spence, S. H., & March, S. (2006). Evidence for retardedextinction of aversive learning in anxious children. Behaviour Research andTherapy, 44(10), 1491–1502.

Linnman, C., Rougemont-Bücking, A., Beucke, J. C., Zeffiro, T. A., & Milad, M. R.(2011). Unconditioned responses and functional fear networks in humanclassical conditioning. Behavioural Brain Research, 221(1), 237–245.

Linnman, C., Zeffiro, T. A., Pitman, R. K., & Milad, M. R. (2011). An fMRI study ofunconditioned responses in post-traumatic stress disorder. Biology of Mood &Anxiety Disorders, 1(1), 8.

Linnman, C., Zeidan, M. A., Furtak, S. C., Pitman, R. K., Quirk, G. J., & Milad, M. R.(2012). Resting amygdala and medial prefrontal metabolism predicts functionalactivation of the fear extinction circuit. The American Journal of Psychiatry,169(4), 415–423.

Linnman, C., Zeidan, M. A., Pitman, R. K., & Milad, M. R. (2013). Resting cerebralmetabolism correlates with skin conductance and functional brain activationduring fear conditioning. Biological Psychology, 92(1), 26–35.

Lipp, O. V., Sheridan, J., & Siddle, D. A. (1994). Human blink startle during aversiveand nonaversive Pavlovian conditioning. Journal of Experimental Psychology.Animal Behavior Processes, 20(4), 380–389.

Lissek, S., Biggs, A. L., Rabin, S. J., Cornwell, B. R., Alvarez, R. P., Pine, D. S., et al.(2008). Generalization of conditioned fear-potentiated startle in humans:Experimental validation and clinical relevance. Behaviour Research andTherapy, 46, 678–687.

Lissek, S., Bradford, D. E., Alvarez, R. P., Burton, P., Espensen-Sturges, T., Reynolds, R.C., et al. (2013). Neural substrates of classically conditioned fear-generalizationin humans: A parametric fMRI study. Social Cognitive and Affective Neuroscience.

Lissek, S., Powers, A. S., McClure, E. B., Phelps, E. A., Woldehawariat, G., Grillon, C.,et al. (2005). Classical fear conditioning in the anxiety disorders: A meta-analysis. Behaviour Research and Therapy, 43(11), 1391–1424.

Litz, B. T., Salters-Pedneault, K., Steenkamp, M. M., Hermos, J. A., Bryant, R. A., Otto,M. W., et al. (2012). A randomized placebo-controlled trial of D-cycloserine andexposure therapy for posttraumatic stress disorder. Journal of PsychiatricResearch, 46(9), 1184–1190.

Lonsdorf, T. B., & Kalisch, R. (2011). A review on experimental and clinical geneticassociations studies on fear conditioning, extinction and cognitive-behavioraltreatment. Translational Psychiatry, 1, e41.

Lonsdorf, T. B., Weike, A. I., Golkar, A., Schalling, M., Hamm, A. O., & Öhman, A.(2010). Amygdala-dependent fear conditioning in humans is modulated by theBDNFval66met polymorphism. Behavioral Neuroscience, 124(1), 9–15.

Lonsdorf, T. B., Weike, A. I., Nikamo, P., Schalling, M., Hamm, A. O., & Öhman, A.(2009). Genetic gating of human fear learning and extinction: Possible


implications for gene–environment interaction in anxiety disorder.Psychological Science, 20(2), 198–206.

Maier, S., Szalkowski, A., Kamphausen, S., Perlov, E., Feige, B., Blechert, J., et al.(2012). Clarifying the role of the rostral dmPFC/dACC in fear/anxiety: Learning,appraisal or expression? PLoS ONE, 7(11), e50120.

Maren, S. (2001). Neurobiology of Pavlovian fear conditioning. Annual Review ofNeuroscience, 24, 897–931.

Maren, S. (2013). Fear of the unexpected: Hippocampus mediates novelty-inducedreturn of extinguished fear in rats. Neurobiology of Learning and Memory, http://dx.doi:10.1016/j.nlm.2013.06.004 [Epub ahead of Print].

Maren, S., Phan, K. L., & Liberzon, I. (2013). The contextual brain: Implications forfear conditioning, extinction and psychopathology. Nature Reviews Neuroscience,14(6), 417–428.

Marschner, A., Kalisch, R., Vervliet, B., Vansteenwegen, D., & Buchel, C. (2008).Dissociable roles for the hippocampus and the amygdala in human cued versuscontext fear conditioning. The Journal of Neuroscience, 28(36), 9030–9036.

Mayou, R. A., Ehlers, A., & Hobbs, M. (2000). Psychological debriefing for road trafficaccident victims. Three-year follow-up of a randomised controlled trial. TheBritish Journal of Psychiatry, 176, 589–593.

Michael, T., Blechert, J., Vriends, N., Margraf, J., & Wilhelm, F. H. (2007). Fearconditioning in panic disorder: Enhanced resistance to extinction. Journal ofAbnormal Psychology, 116(3), 612–617.

Milad, M. R., Furtak, S. C., Greenberg, J. L., Keshaviah, A., Im, J. J., Falkenstein, M. J.,et al. (2013). Deficits in conditioned fear extinction in obsessive–compulsivedisorder and neurobiological changes in the fear circuit. JAMA Psychiatry, 70(6),608–618.

Milad, M. R., Orr, S. P., Lasko, N. B., Chang, Y., Rauch, S. L., & Pitman, R. K. (2008).Presence and acquired origin of reduced recall for fear extinction in PTSD:Results of a twin study. Journal of Psychiatric Research, 42(7), 515–520.

Milad, M. R., Orr, S. P., Pitman, R. K., & Rauch, S. L. (2005). Context modulation ofmemory for fear extinction in humans. Psychophysiology, 42(4), 456–464.

Milad, M. R., Pitman, R. K., Ellis, C. B., Gold, A. L., Shin, L. M., Lasko, N. B., et al. (2009).Neurobiological basis of failure to recall extinction memory in posttraumaticstress disorder. Biological Psychiatry, 66(12), 1075–1082.

Milad, M. R., & Quirk, G. J. (2002). Neurons in medial prefrontal cortex signalmemory for fear extinction. Nature, 420(6911), 70–74.

Milad, M. R., & Quirk, G. J. (2012). Fear extinction as a model for translationalneuroscience. Ten years of progress. Annual Review of Psychology, 63(1),129–151.

Milad, M. R., Quirk, G. J., Pitman, R. K., Orr, S. P., Fischl, B., & Rauch, S. L. (2007). A rolefor the human dorsal anterior cingulate cortex in fear expression. BiologicalPsychiatry, 62(10), 1191–1194.

Milad, M. R., Rauch, S. L., Pitman, R. K., & Quirk, G. J. (2006). Fear extinction in rats:Implications for human brain imaging and anxiety disorders. BiologicalPsychology, 73(1), 61–71.

Milad, M. R., Vidal-Gonzalez, I., & Quirk, G. J. (2004). Electrical stimulation of medialprefrontal cortex reduces conditioned fear in a temporally specific manner.Behavioral Neuroscience, 118(2), 389–394.

Milad, M. R., Wright, C. I., Orr, S. P., Pitman, R. K., Quirk, G. J., & Rauch, S. L. (2007).Recall of fear extinction in humans activates the ventromedial prefrontal cortexand hippocampus in concert. Biological Psychiatry, 62(5), 446–454.

Milekic, M. H., & Alberini, C. M. (2002). Temporally graded requirement for proteinsynthesis following memory reactivation. Neuron, 36(3), 521–525.

Monfils, M.-H., Cowansage, K. K., Klann, E., & LeDoux, J. E. (2009). Extinction–reconsolidation boundaries: Key to persistent attenuation of fear memories.Science, 324(5929), 951–955.

Moores, K. A., Clark, C. R., McFarlane, A. C., Brown, G. C., Puce, A., & Taylor, D. J.(2008). Abnormal recruitment of working memory updating networks duringmaintenance of trauma-neutral information in post-traumatic stress disorder.Psychiatry Research, 163(2), 156–170.

Morgan, C. A., Grillon, C., Southwick, S. M., Davis, M., & Charney, D. S. (1995). Fear-potentiated startle in posttraumatic stress disorder. Biological Psychiatry, 38(6),378–385.

Morris, J. S., & Dolan, R. J. (2004). Dissociable amygdala and orbitofrontal responsesduring reversal fear conditioning. NeuroImage, 22(1), 372–380.

Morris, S. E., & Cuthbert, B. N. (2012). Research domain criteria: Cognitive systems,neural circuits, and dimensions of behavior. Dialogues in Clinical Neuroscience,14(1), 29–37.

Myers, K. M., & Davis, M. (2004). AX+, BX� discrimination learning in the fear-potentiated startle paradigm: Possible relevance to inhibitory fear learning inextinction. Learning & Memory, 11, 464–475.

Myers, K. M., & Davis, M. (2007). Mechanisms of fear extinction. MolecularPsychiatry, 12(2), 120–150.

Nader, K., & Hardt, O. (2009). A single standard for memory: The case forreconsolidation. Nature Reviews Neuroscience, 10(3), 224–234.

Nader, K., Schafe, G. E., & Le Doux, J. E. (2000). Fear memories require proteinsynthesis in the amygdala for reconsolidation after retrieval. Nature, 406(6797),722–726.

Norberg, M. M., Krystal, J. H., & Tolin, D. F. (2008). A meta-analysis of D-cycloserineand the facilitation of fear extinction and exposure therapy. BiologicalPsychiatry, 63(12), 1118–1126.

Norrholm, S. D., Jovanovic, T., Olin, I. W., Sands, L. A., Karapanou, I., Bradley, B., et al.(2011). Fear extinction in traumatized civilians with posttraumatic stressdisorder: Relation to symptom severity. Biological Psychiatry, 69(6), 556–563.

Norrholm, S. D., Jovanovic, T., Smith, A. K., Binder, E., Klengel, T., Conneely, K., et al.(2013). Differential genetic and epigenetic regulation of catechol-O-



methyltransferase is associated with impaired fear inhibition in posttraumaticstress disorder. Frontiers in Behavioral Neuroscience, 7, 30.

Offringa, R., Handwerger Brohawn, K., Staples, L. K., Dubois, S. J., Hughes, K. C., Pfaff,D. L., et al. (2013). Diminished rostral anterior cingulate cortex activation duringtrauma-unrelated emotional interference in PTSD. Biology of Mood & AnxietyDisorders, 3(1), 10.

Orr, S. P., Metzger, L. J., Lasko, N. B., Macklin, M. L., Peri, T., & Pitman, R. K. (2000). Denovo conditioning in trauma-exposed individuals with and withoutposttraumatic stress disorder. Journal of Abnormal Psychology, 109(2), 290–298.

Osuch, E. A., Benson, B. E., Luckenbaugh, D. A., Geraci, M., Post, R. M., & McCann, U.(2009). Repetitive TMS combined with exposure therapy for PTSD: Apreliminary study. Journal of Anxiety Disorders, 23(1), 54–59.

Otto, M. W., McHugh, R. K., Simon, N. M., Farach, F. J., Worthington, J. J., & Pollack, M.H. (2010). Efficacy of CBT for benzodiazepine discontinuation in patients withpanic disorder: Further evaluation. Behaviour Research and Therapy, 48(8),720–727.

Parsons, R. G., & Ressler, K. J. (2013). Implications of memory modulation for post-traumatic stress and fear disorders. Nature Neuroscience, 16(2), 146–153.

Pavlov, I. P. (1927). Conditioned reflexes: An investigation of the physiological activityof the cerebral cortex. London: Oxford University Press.

Peña, D. F., Engineer, N. D., & McIntyre, C. K. (2013). Rapid remission of conditionedfear expression with extinction training paired with vagus nerve stimulation.Biological Psychiatry, 73(11), 1071–1077.

Peri, T., Ben-Shakhar, G., Orr, S. P., & Shalev, A. Y. (2000). Psychophysiologicassessment of aversive conditioning in posttraumatic stress disorder. BiologicalPsychiatry, 47(6), 512–519.

Phelps, E. A., Delgado, M. R., Nearing, K. I., & LeDoux, J. E. (2004). Extinction learningin humans: Role of the amygdala and vmPFC. Neuron, 43(6), 897–905.

Phelps, E. A., O’Connor, K. J., Gatenby, J. C., Gore, J. C., Grillon, C., & Davis, M. (2001).Activation of the left amygdala to a cognitive representation of fear. NatureNeuroscience, 4(4), 437–441.

Phillips, R. G., & LeDoux, J. E. (1992). Differential contribution of amygdala andhippocampus to cued and contextual fear conditioning. Behavioral Neuroscience,106(2), 274–285.

Pine, D. S., Fyer, A., Grun, J., Phelps, E. A., Szeszko, P. R., Koda, V., et al. (2001).Methods for developmental studies of fear conditioning circuitry. BiologicalPsychiatry, 50(3), 225–228.

Pitkanen, A. (2000). Connectivity of the rat amygdaloid complex. In J. P. Aggleton(Ed.), The amygdala: A functional analysis (2nd ed.. New York: Oxford UniversityPress.

Pitman, R. K. (2011). Will reconsolidation blockade offer a novel treatment forposttraumatic stress disorder? Frontiers in Behavioral Neuroscience, 5, 11.

Pitman, R. K., Milad, M. R., Igoe, S. A., Vangel, M. G., Orr, S. P., Tsareva, A., et al.(2011). Systemic mifepristone blocks reconsolidation of cue-conditioned fear;propranolol prevents this effect. Behavioral Neuroscience, 125(4), 632–638.

Pitman, R. K., & Orr, S. P. (1986). Test of the conditioning model of neurosis:Differential aversive conditioning of angry and neutral facial expressions inanxiety disorder patients. Journal of Abnormal Psychology, 95(3), 208–213.

Pitman, R. K., Rasmusson, A. M., Koenen, K. C., Shin, L. M., Orr, S. P., Gilbertson, M.W., et al. (2012). Biological studies of post-traumatic stress disorder. NatureReviews Neuroscience, 13(11), 769–787.

Rabinak, C. A., Angstadt, M., Sripada, C. S., Abelson, J. L., Liberzon, I., Milad, M. R.,et al. (2013). Cannabinoid facilitation of fear extinction memory recall inhumans. Neuropharmacology, 64, 396–402.

Raczka, K. A., Mechias, M.-L., Gartmann, N., Reif, A., Deckert, J., Pessiglione, M., et al.(2011). Empirical support for an involvement of the mesostriatal dopaminesystem in human fear extinction. Translational Psychiatry, 1, e12.

Rauch, S. L., Shin, L. M., & Phelps, E. A. (2006). Neurocircuitry models ofposttraumatic stress disorder and extinction: Human neuroimaging research– Past, present, and future. Biological Psychiatry, 60(4), 376–382.

Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P., Graap, K., Zimand, E.,et al. (2004). Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinction of fear. Archives ofGeneral Psychiatry, 61(11), 1136–1144.

Resstel, L. B. M., Joca, S. R. L., Guimarães, F. G., & Corrêa, F. M. A. (2006). Involvementof medial prefrontal cortex neurons in behavioral and cardiovascular responsesto contextual fear conditioning. Neuroscience, 143(2), 377–385.

Rothbaum, B. O., & Davis, M. (2003). Applying learning principles to the treatmentof post-trauma reactions. Annals of the New York Academy of Sciences, 1008,112–121.

Rothbaum, B. O., Hodges, L., Alarcon, R., Ready, D., Shahar, F., Graap, K., et al. (1999).Virtual reality exposure therapy for PTSD Vietnam Veterans: A case study.Journal of Traumatic Stress, 12(2), 263–271.

Rothbaum, B. O., Kearns, M. C., Price, M., Malcoun, E., Davis, M., Ressler, K. J., et al.(2012). Early intervention may prevent the development of posttraumaticstress disorder: A randomized pilot civilian study with modified prolongedexposure. Biological Psychiatry, 72(11), 957–963.

Rougemont-Bücking, A., Linnman, C., Zeffiro, T. A., Zeidan, M. A., Lebron-Milad, K.,Rodriguez-Romaguera, J., et al. (2011). Altered processing of contextualinformation during fear extinction in PTSD: An fMRI study. CNS Neuroscience& Therapeutics, 17(4), 227–236.

Rubin, D. C., Berntsen, D., & Bohni, M. K. (2008). A memory-based model ofposttraumatic stress disorder: Evaluating basic assumptions underlying thePTSD diagnosis. Psychological Review, 115(4), 985–1011.

Rudy, J. W. (2008). The neurobiology of learning and memory. Sunderland,Massachusetts: Sinauer Associates.


Rudy, J. W. (2009). Context representations, context functions, and theparahippocampal–hippocampal system. Learning & Memory, 16(10), 573–585.

Rudy, J. W., Huff, N. C., & Matus-Amat, P. (2004). Understanding contextual fearconditioning: Insights from a two-process model. Neuroscience andBiobehavioral Reviews, 28(7), 675–685.

Rudy, J. W., & O’Reilly, R. C. (2001). Conjunctive representations, the hippocampus,and contextual fear conditioning. Cognitive, Affective, & Behavioral Neuroscience,1(1), 66–82.

Rudy, J. W., & Tyler, T. J. (2010). Episodic memory and the hippocampus. The CorsiniEncyclopedia of Psychology, 1–2.

Schneider, F., Weiss, U., Kessler, C., Müller-Gärtner, H. W., Posse, S., Salloum, J. B.,et al. (1999). Subcortical correlates of differential classical conditioning ofaversive emotional reactions in social phobia. Biological Psychiatry, 45(7),863–871.

Schneier, F. R., Neria, Y., Pavlicova, M., Hembree, E., Suh, E. J., Amsel, L., et al. (2012).Combined prolonged exposure therapy and paroxetine for PTSD related to theWorld Trade Center attack: A randomized controlled trial. The American Journalof Psychiatry, 169(1), 80–88.

Schultz, D. H., Balderston, N. L., & Helmstetter, F. J. (2012). Resting-stateconnectivity of the amygdala is altered following Pavlovian fear conditioning.Frontiers in Human Neuroscience, 6, 242.

Sehlmeyer, C., Schöning, S., Zwitserlood, P., Pfleiderer, B., Kircher, T., Arolt, V., et al.(2009). Human fear conditioning and extinction in neuroimaging: A systematicreview. PLoS ONE, 4(6), e5865.

Shin, L. M., Bush, G., Milad, M. R., Lasko, N. B., Brohawn, K. H., Hughes, K. C., et al.(2011). Exaggerated activation of dorsal anterior cingulate cortex duringcognitive interference: A monozygotic twin study of posttraumatic stressdisorder. The American Journal of Psychiatry, 168(9), 979–985.

Shin, L. M., Bush, G., Whalen, P. J., Handwerger, K., Cannistraro, P. A., Wright, C. I.,et al. (2007). Dorsal anterior cingulate function in posttraumatic stress disorder.Journal of Traumatic Stress, 20(5), 701–712.

Shin, L. M., & Handwerger, K. (2009). Is posttraumatic stress disorder a stress-induced fear circuitry disorder? Journal of Traumatic Stress, 22(5), 409–415.

Shin, L. M., Lasko, N. B., Macklin, M. L., Karpf, R. D., Milad, M. R., Orr, S. P., et al.(2009). Resting metabolic activity in the cingulate cortex and vulnerability toposttraumatic stress disorder. Archives of General Psychiatry, 66(10), 1099–1107.

Shin, L. M., & Liberzon, I. (2010). The neurocircuitry of fear, stress, and anxietydisorders. Neuropsychopharmacology, 35(1), 169–191.

Shin, L. M., McNally, R. J., Kosslyn, S. M., Thompson, W. L., Rauch, S. L., Alpert, N. M.,et al. (1999). Regional cerebral blood flow during script-driven imagery inchildhood sexual abuse-related PTSD: A PET investigation. The American Journalof Psychiatry, 156(4), 575–584.

Shin, L. M., Orr, S. P., Carson, M. A., Rauch, S. L., Macklin, M. L., Lasko, N. B., et al.(2004). Regional cerebral blood flow in the amygdala and medial prefrontalcortex during traumatic imagery in male and female Vietnam veterans withPTSD. Archives of General Psychiatry, 61(2), 168–176.

Shumyatsky, G. P., Malleret, G., Shin, R.-M., Takizawa, S., Tully, K., Tsvetkov, E., et al.(2005). Stathmin, a gene enriched in the amygdala, controls both learned andinnate fear. Cell, 123(4), 697–709.

Skelton, K., Ressler, K. J., Norrholm, S. D., Jovanovic, T., & Bradley-Davino, B. (2011).PTSD and gene variants: New pathways and new thinking. Neuropharmacology,62(2), 628–637.

Smits, J. A. J., Rosenfield, D., Otto, M. W., Powers, M. B., Hofmann, S. G., Telch, M. J.,et al. (2013). D-Cycloserine enhancement of fear extinction is specific tosuccessful exposure sessions: Evidence from the treatment of height phobia.Biological Psychiatry, 73(11), 1054–1058.

Sokolowska, E., & Hovatta, I. (2013). Anxiety genetics – Findings from cross-speciesgenome-wide approaches. Biology of Mood & Anxiety Disorders, 3(1), 9.

Soliman, F., Glatt, C. E., Bath, K. G., Levita, L., Jones, R. M., Pattwell, S. S., et al. (2010).A genetic variant BDNF polymorphism alters extinction learning in both mouseand human. Science, 327(5967), 863–866.

Somerville, L. H., Whalen, P. J., & Kelley, W. M. (2010). Human bed nucleus of thestria terminalis indexes hypervigilant threat monitoring. Biological Psychiatry,68(5), 416–424.

Squire, L. R., & Zola-Morgan, S. (1991). The medial temporal lobe memory system.Science, 253(5026), 1380–1386.

Surís, A., North, C., Adinoff, B., Powell, C. M., & Greene, R. (2010). Effects ofexogenous glucocorticoid on combat-related PTSD symptoms. Annals of ClinicalPsychiatry, 22(4), 274–279.

Tabbert, K., Stark, R., Kirsch, P., & Vaitl, D. (2006). Dissociation of neural responsesand skin conductance reactions during fear conditioning with and withoutawareness of stimulus contingencies. NeuroImage, 32(2), 761–770.

Thompson, B. M., Baratta, M. V., Biedenkapp, J. C., Rudy, J. W., Watkins, L. R., & Maier,S. F. (2010). Activation of the infralimbic cortex in a fear context enhancesextinction learning. Learning & Memory, 17(11), 591–599.

Tyler, W. J., Alonso, M., Bramham, C. R., & Pozzo-Miller, L. D. (2002). Fromacquisition to consolidation: On the role of brain-derived neurotrophic factorsignaling in hippocampal-dependent learning. Learning & Memory, 9(5),224–237.

VanElzakker, M. B., Fevurly, R. D., Breindel, T., & Spencer, R. L. (2008). Environmentalnovelty is associated with a selective increase in Fos expression in the outputelements of the hippocampal formation and the perirhinal cortex. Learning &Memory, 15(12), 899–908.

VanElzakker, M. B., Staples, L. K., & Shin, L. M. (in press). The neurocircuitry of fearand PTSD. In E. Vermetten, T. C. Neylan, S. R. Pandi-Perumal, & M. Kramer (Eds.).New York: Springer-Verlag.



Vertes, R. P. (2004). Differential projections of the infralimbic and prelimbic cortexin the rat. Synapse, 51(1), 32–58.

Watson, J. B., & Rayner, R. (2000). Conditioned emotional reactions. 1920. TheAmerican Psychologist, 55(3), 313–317.

Weiss, D. S., Marmar, C. R., Schlenger, W. E., Fairbank, J. A., Jordan, B. K., Hought, R. L.,et al. (1992). The prevalence of lifetime and partial post-traumatic stressdisorder in Vietnam theater veterans. Journal of Traumatic Stress, 5(3), 1–12.

Wilhelm, S., Buhlmann, U., Tolin, D. F., Meunier, S. A., Pearlson, G. D., Reese, H. E.,et al. (2008). Augmentation of behavior therapy with D-cycloserine forobsessive–compulsive disorder. The American Journal of Psychiatry, 165(3),335–341.

Williams, L. M., Kemp, A. H., Felmingham, K., Barton, M., Olivieri, G., Peduto, A., et al.(2006). Trauma modulates amygdala and medial prefrontal responses toconsciously attended fear. NeuroImage, 29(2), 347–357.

Woon, F. L., Sood, S., & Hedges, D. W. (2010). Hippocampal volume deficitsassociated with exposure to psychological trauma and posttraumatic stress


disorder in adults: A meta-analysis. Progress in Neuro-Psychopharmacology &Biological Psychiatry, 34(7), 1181–1188.

Yang, C.-H., Shi, H.-S., Zhu, W.-L., Wu, P., Sun, L.-L., Si, J.-J., et al. (2012). Venlafaxinefacilitates between-session extinction and prevents reinstatement of auditory-cue conditioned fear. Behavioural Brain Research, 230(1), 268–273.

Yang, Y.-L., Chao, P.-K., & Lu, K.-T. (2006). Systemic and intra-amygdalaadministration of glucocorticoid agonist and antagonist modulate extinctionof conditioned fear. Neuropsychopharmacology, 31(5), 912–924.

Yehuda, R., & LeDoux, J. (2007). Response variation following trauma: A translationalneuroscience approach to understanding PTSD. Neuron, 56(1), 19–32.

Zimmerman, J. M., & Maren, S. (2010). NMDA receptor antagonism in thebasolateral but not central amygdala blocks the extinction of Pavlovian fearconditioning in rats. The European Journal of Neuroscience, 31(9), 1664–1670.

Zoladz, P. R., & Diamond, D. M. (2013). Current status on behavioral and biologicalmarkers of PTSD: A search for clarity in a conflicting literature. Neuroscience andBiobehavioral Reviews, 37(5), 860–895.


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