Learning Models of PTSD: Theoretical Accounts and Psychobiological Evidence

International Journal of Psychophysiology 98 (2015) 594–605

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International Journal of Psychophysiology

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

Review Learning models of PTSD: Theoretical accounts and psychobiological evidence

Shmuel Lissek ⁎, Brian van Meurs

University of Minnesota—Twin Cities Campus, Department of Psychology, 75 East River Road, Minneapolis, MN 55455, United States article info abstract

Article history: Learning abnormalities have long been centrally implicated in posttraumatic psychopathology. Indeed, of all anx- Received 26 May 2014 iety disorders, PTSD may be most clearly attributable to discrete, aversive learning events. In PTSD, such learning Received in revised form 29 October 2014 is acquired during the traumatic encounter and is expressed as both conditioned fear to stimuli associated with Accepted 10 November 2014 the event and more general over-reactivity—or failure to adapt—to intense, novel, or fear-related stimuli. The rel- Available online 20 November 2014 atively straightforward link between PTSD and these basic, evolutionarily old, learning processes of conditioning,

Keywords: sensitization, and habituation affords models of PTSD comprised of fundamental, experimentally tractable mech- PTSD anisms of learning that have been well characterized across a variety of mammalian species including humans. Fear-conditioning Though such learning mechanisms have featured prominently in explanatory models of psychological maladjust- Extinction ment to trauma for at least 90 years, much of the empirical testing of these models has occurred only in the past Overgeneralization two decades. The current review delineates the variety of theories forming this longstanding tradition of Sensitization learning-based models of PTSD, details empirical evidence for such models, attempts an integrative account of Habituation results from this literature, and speciﬁes limitations of, and future directions for, studies testing learning models of PTSD. © 2014 Elsevier B.V. All rights reserved.

1. Introduction the variety of learning mechanisms implicated in the onset and maintenance of PTSD through outlining associative- and non-associative- From the learning perspective, symptoms of PTSD stem largely from learning models of PTSD; detailing extant empirical support for such maladaptive learning occurring during and after a traumatic encounter. models; and delineating the research limitations and future directions Such learning manifests in both associative and non-associative forms. for the field. A summary of learning-based theories of PTSD is provided Through associative fear-conditioning (Pavlov, 1927), neutral stimuli in Table 1. (people, places, and things) associated with the aversive trauma acquire From the outset, it should be noted that this review does not the capacity to trigger and maintain anxiety well after the occurrence of comprise an exhaustive examination of all relevant empirical findings. the traumatic episode. This conditioning process is thought to contrib- Rather, this review is theoretically driven, in that it endeavors to de- ute centrally to the re-experiencing (e.g., distressing recollections) and scribe the weight of the evidence for and against all prevalent learning- avoidance symptom-clusters that are often triggered by exposure to based theories of PTSD. Search terms used for retrieval of articles thus in- stimuli that resemble aspects of the trauma, but are in fact indicative cluded ‘traumatic stress’ plus theory-specifictermssuchas:‘resistance to of no genuine danger. Maladaptive forms of non-associative learning extinguish’, ‘extinction’,or‘extinction recall’; ‘conditionability’, ‘incuba- in PTSD are evidenced by broad anxious reactivity—to novel, intense, tion’,or‘acquisition of conditioned fear’; ‘associative learning deficits’, or fear-relevant stimuli in the environment—that is both resistant to ‘contextual anxiety’,or‘unpredictable threat’; ‘two-stage learning’ or degradation via habituation, and susceptible to intensification through ‘avoidance’; ‘generalization’; ‘failure to inhibit’ or ‘conditioned inhibition’; sensitization. These non-associative learning correlates of PTSD promote ‘habituation’; and ‘sensitization’,or‘kindling’. This approach was de- sustained sympathetic activation thought to result in such hyperarousal signed to ensure retrieval of articles covering all prevailing learning- symptoms of PTSD as hypervigilance, exaggerated startle, difficulty based theories of PTSD. concentrating and irritability. In this review, we will explore, in depth, 2. Associative fear-learning

Fear-conditioning—the associative learning process whereby a natu- ⁎ Corresponding author at: University of Minnesota, Department of Psychology, Elliott rally benign conditioned stimulus (CS) acquires anxiogenic properties Hall, Rm# N416, 75 East River Road, Minneapolis, MN 55455, United States. Tel.: +1 612 720 3152. by virtue of its pairing with a naturally aversive unconditioned stimulus E-mail address: [email protected] (S. Lissek). (US)—has ﬁgured prominently in accounts of maladaptive psychological

Table 1 Delineation of learning based theories of PTSD, clinical illustrations, and empirical evidence.

Theory Thesis Clinical vignette Lab-based evidence A USA combat veteran with PTSD acquired Pavlovian fear to a roadside object (CS+) used to encase an improvised explosive device (US) by which he was injured while on street patrol in Iraq.

I. Associative 1. Resistance to The persistence of conditioned fear to CS+ Though, upon return to civilian life in the USA, • Inconsistent evidence for impaired acqui- Extinction that are no longer indicative of this veteran's initial display of conditioned fear sition of extinction learning in PTSD. environmental danger (i.e., CS+ no longer to roadside objects (CS+) would be considered • Accumulating support for impaired recall paired with the US), contributes to PTSD normative, if this veteran fails to extinguish of extinction learning over time in PTSD. symptomatology. fear through repeated exposures to benign roadside objects (trash, debris, fire hydrants), conditioned fear would pathogenically contribute to his post-deployment functioning. 1a. Increased fear Individuals with, or at risk for PTSD have a If this soldier forms overly strong associations • Little support from empirical literature as excitation heightened tendency to form aversive between roadside objects (CS+) and the most lab-based studies do not show (hyper-conditionability) associations reflectedbyabnormallystrong explosion (US), upon return to the USA the heightened fear conditioning to the CS+ in excitatory fear-conditioning to the CS+, roadside objects will be particularly salient PTSD. resulting in resistance to extinguish fear to the trauma cues that will resist extinction via CS+. exposures to roadside objects in the absence of the US, and thereby maintain traumatic fear over time. Heightened excitatory fear-conditioning in Upon return to the USA, the veteran's • No evidence. 1b. Incubation those with, or at risk for PTSD results in a CR conditioned fear response to roadside objects is (fear) that is aversive enough to serve as a sufficiently acute and aversive to serve as a ‘US US-substitute. In turn, the CR continues to substitute’ that continues to aversively reinforce the CS+ in the absence of US reinforce the CS+ (roadside objects) in the pairings, blocking extinction, and perhaps even absence of the US (explosions). This prevents ‘incubating’, or enhancing, the conditioned fear the veteran from extinguishing fear to the CS+ response with repeated, unpaired CS+ and may result in enhanced conditioned fear exposures. responses over time. 1c. Two-stage learning Heightened Pavlovian fear in those with, or Strong Pavlovian fear to roadside objects • No evidence. at risk for PTSD (Stage 1) is proposed to act motivates the returning veteran to avoid driving as a drive that motivates and reinforces or walking on streets to avert conditioned fear avoidance of the CS+ (Stage 2). Such elicited by roadside objects. By so doing, the avoidance prevents extinction by denying veteran is denied the opportunity to extinguish the individual future opportunities to this conditioned response, in their now safe experience the CS+ in the absence of the US. post-deployment environment, through exposure to roadside objects in the absence of dangerous outcomes. 1d. Reduced fear inhibition Individuals with, or at risk for PTSD have an The veteran's memories of post-deployment • Theory supported by fMRI data linking impaired ability to inhibit fear to CSs exposures to roadside objects, in the absence of poor retention of extinction in PTSD to previously, but no longer, paired with an any aversive outcomes, are insufficiently strong under-functioning mPFC: a brain region aversive US, blocking or retarding extinction to inhibit the excitatory fear memory of the contributing to fear reduction through in- of conditioned fear. CS–US association acquired in Iraq, resulting in hibition of amygdaloid neurons. a failure to extinguish fear. 2. Associative learning The impaired ability to learn environmental While still in Iraq, the veteran fails to distinguish • Mixed evidence for associative learning deficits & sustained cues(CS+)ofdanger(US)deniesthosewith, between danger and safety due to insufficient deficits in PTSD. contextual anxiety or at risk for PTSD the awareness of safety learning of danger cues. This leads to chronic anx- • Substantial lab-based evidence of height- periods, resulting in chronic anxiety. Further, iety during deployment and heightened contextu- ened contextual anxiety in PTSD. the unawareness of danger cues leads the al anxiety to the deployment environment, which individual to more generally associate the are both risk factors for PTSD. unpleasant US with the environment in which the US is experienced, resulting in heightened contextual anxiety. 3. Over-generalization A heightened tendency among those with, or Though conditioned-fear was acquired to a • Preliminary support derives from differen- at risk for PTSD, to transfer conditioned fear particular encasement of a roadside explosive tial conditioning studies in PTSD evidenc- from the CS + to stimuli resembling the device, upon return to the USA the veteran's fears ing heightened fear reactivity to CS− CS+. Such over-generalization results in the may generalize to such ‘benign’ roadside objects sharing multiple stimulus features undue spreading of conditioned fear to as trash cans, fire hydrants, or other roadside (e.g., shape, size, duration, spatial loca- stimuli that resemble features of the debris. This may promote frequent trauma-related tion) with the conditioned danger-cue. traumatic encounter. anxiety in his benign posttraumatic environment • Recent support from ‘generalization gradi- because these roadside objects are ubiquitous in ent’ studies identifying less steep gradi- his neighborhood and town. ents of generalization in PTSD. 4. Failure to inhibit fear in the A compromised capacity for fear inhibition Upon return to the USA, the veteran encounters • Support derives from ‘conditional discrim- presence of safety cues results in the failure to suppress fear in the roadside objects (CS+) coincident with many ination’ findings of impaired inhibition of presence of safety cues, and maintains fear potential environmental cues of safety fear to a conditioned danger-cue when responding during periods of safety among including neighborhood people, shops, parks, presented in tandem with a conditioned those with, or at risk for PTSD. and houses. These safety cues are however safety-cue among PTSD patients. unable to exert inhibitory control over the • Additional support is provided by neuro- conditioned response to roadside objects imaging studies documenting reduced ac- leading to a continuation of the traumatic tivation in brain areas associated with fear response in the benign, civilian context. inhibition (mPFC) among those with, versus without, PTSD during exposure to traumatic pictures and sounds, script driven traumatic imagery, and fearful faces.

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Table 1 (continued)

II. Nonssociative 1. Failure-to-habituate Trauma induces an impaired ability to Upon return to the USA, this veteran may • Supported by the well replicated finding of autonomically adapt, or habituate, to display persistent autonomic responding to less steep habituation slopes, measured intense, novel, or fear-relevant reoccurring, and more or less irrelevant, via SCR (but not HR or startle EMG) to environmental stimuli (whether or not they sensory stimuli (sounds, sights, touches), as intense acoustic tones. resemble aspects of the trauma) among displayed by exaggerated startle responses and those with, or at risk for PTSD. The failure of hypervigilance. Additionally, the inability to this type of habituation is proposed as a filter out these reoccurring sensory stimuli central contributor to the hyper-arousal compromises concentration by exhausting cluster of PTSD symptoms. attentional resources otherwise available for processing more consequential stimulus events. 2. Stress sensitization Trauma induces autonomic Upon return to the USA, this veteran may • Supported by replicated findings of in- hyper-excitability (i.e., stress sensitization) display increasing autonomic responding to creased HR (and SCR and startle EMG to to intense, novel, or fear related stimuli reoccurring, and more or less irrelevant, some degree) responses to repeatedly (whether or not they resemble aspects of the sensory stimuli (sounds, sights, touches), presented, high intensity noises in those trauma) among those with, or at risk for resulting in the same hyper-arousal symptoms with vs. without PTSD. PTSD. This hyper-excitability is proposed as described above for habituation failure an underlying mechanism for the hyper-- (exaggerated startle, hypervigilance, poor arousal cluster of PTSD symptoms. concentration). 2a. Amygdala kindling A variant of stress sensitization theory in Because of trauma-related kindling of this • Supported by replicated neuroimaging which the traumatic experience is proposed veteran's fear circuit, upon return to the US, he findings of stronger amygdala activation to to stimulate, or kindle, the amygdala-based displays heightened anxiety to fear-relevant fearful and neutral faces in those with vs. fear circuit rendering the fear system stimuli contributing to the maintenance of without PTSD. hyper-excitable to either future trauma or PTSD symptomatology. • Epileptic discharges in the human tempo- fear-relevant stimuli. ral lobe (the cerebral structure encasing the amygdala) are associated with marked increases in reported fear and anxiety.

CS+ = conditioned danger-cue; CS− = conditioned safety-cue; US = unconditioned stimulus; CR = conditioned response; EMG = electromyography; HR = heart-rate; SCR = skin conductance response; fMRI = functional magnetic resonance imaging; mPFC = medial prefrontal cortex. reactions to trauma for at least 90 years (Pavlov, 1927; Watson and disposition toward forming aversive associations instantiated by abnor- Rayner, 1920). During this period, a variety of mechanisms through mally strong acquisition and a resulting resistance to extinguish. The which fear-conditioning exerts pathological influence have been theo- second mechanism is reflected in theories by Davis et al. (2000) and rized, including: 1) resistance to extinguish conditioned fear, 2) Mowrer's Jovanovic and Ressler (2010) linking PTSD to deficits in extinction, two-stage learning, 3) stimulus generalization, 4) hyper-conditionability, and other forms of inhibitory fear learning, resulting in the failure to and 5) associative-learning deficits leading to contextual anxiety. suppress what are otherwise normative levels of fear acquisition. An additional formulation of the extinction model comes from 2.1. Resistance to extinction Eysenck (1979) who argues that the conditioned response (i.e., an internal state of fear) is sufficiently “nocive” or uncomfortable in those dis- Many conditioning models of PTSD posit a resistance to extinguish posed toward clinical anxiety to serve as an aversive US-substitute in conditioned fear as the central pathogen. In the context of fear- the absence of the genuine US. That is, extinction of fear to a CS previously conditioning, extinction refers to a decline in fear responding to a condi- paired with an aversive outcome may be slowed or prevented in those for tioned danger-cue (i.e., CS) presented one or more times in the absence whom anxiety reactions to the CS are sufficiently strong to function as of the aversive US. Failure to extinguish entails the persistence of fear to aversive reinforcement of the CS during extinction learning. Eysenck stimuli that are no longer indicative of environmental danger and thus not only predicts slowed extinction but goes further by expecting a constitutes a maladaptive expression of anxiety. Importantly, extinction kind of “incubation”, or enhancement of the conditioned fear response, is a new learning that inhibits, rather than erases, the acquired CS/US as- in the absence of the genuine US, in those disposed to anxiety. Such incu- sociation (for a review, see Bouton, 2004). Specifically, extinction in- bation is proposed to operate through a positive feedback loop whereby volves the encoding of a second learning experience with the CS repeated reinforcement of the CS by the fear response strengthens the (i.e., the CS as benign) that competes for activation with the original ac- aversive valence of the CS, which subsequently increases levels of fearful quisition learning experience (i.e., the CS as a signal of danger: Bouton CS-reactivity and provides further aversive reinforcement of the CS. and Swartzentruber, 1991). Extinction of conditioned responding oc- To illustrate extinction-failure in the context of PTSD, consider the curs only when the extinction learning is strong enough to outcompete example of a combat soldier who acquires conditioned fear to a road- the fear memory encoded at acquisition for activation (see Fig. 1). side, box-shaped object (CS) used to encase an improvised explosive From this competition-theory perspective, extinction accounts of device (US) by which he is injured while on street patrol in Iraq. Though, PTSD are derived from two mechanisms through which the inhibitory upon return to civilian life, the initial display of conditioned fear to road- influences of extinction are outstripped by excitatory influences of side objects is normative, failure to extinguish fear through repeated ex- fear acquisition. The first results from elevated levels of acquisition posure to benign roadside objects (i.e., the CS in the absence of the US) is that overpower the inhibitory effects of extinction. The second involves thought to be the maladaptive consequence of either: 1) an overly adeficit in extinction (inhibitory) learning that confers a competitive strong acquisition memory (i.e., conditionability hypothesis), 2) an insuf- edge to the fear acquisition memory. Drawing from the first of these ficiently strong extinction memory (i.e., failure-to-inhibit hypothesis), or two mechanisms, the conditionability theory by Pitman and colleagues 3) an especially nocive conditioned response that continues to aversive- (e.g., Orr et al., 2000) imputes PTSD to hyper-conditionability: a ly reinforce roadside objects (i.e., incubation hypothesis). S. Lissek, B. van Meurs / International Journal of Psychophysiology 98 (2015) 594–605 597

More recently, interest has accrued in studying PTSD–control differences in retention of extinction learning over time (Milad et al., Extinction as Competitive, 2008; Milad et al., 2009; Orr et al., 2006; Shvil et al., 2014). Two of Inhibitory Learning three such studies document impaired recall of extinction learning in PTSD patients during the second day of testing, in the absence of abnormalities in the original extinction learning (Milad et al., 2008; Milad et al., 2009). Recently, a fourth such study demonstrated defi- inhibition cits in extinction recall in male but not in female patients with PTSD (Shvil et al., 2014). Twin data from one study (Milad et al., 2008) characterizes deficientextinctionrecallinPTSDasaconsequence ACQ Memory EXT Memory of traumatic exposure rather than a preexisting risk factor. Such findings link PTSD to an intact ability to extinguish conditioned fear during the course of extinction (exposure) training, but a US fi Time 1(AM) CS US Time 2(PM) trauma-induced impairment in maintaining bene ts of this training over time. Whether impaired extinction-recall emerges as a more replicable marker of PTSD awaits further testing. For now these results seem to highlight the importance of repeated follow-up assessments of PTSD, and repeated treatment sessions if needed, for patients undergoing exposure-based treatments. As portrayed in Fig. 1, the competition theory of extinction im- plies two mechanisms by which extinction failure might occur: no fear 1) an overly strong acquisition memory of the CS as threatening fear that is refractory to the inhibitory effects of the extinction memory, (i.e., extinction) as implied by the hyper-conditionability theory (e.g., Orr et al., 2000); or 2) an insufficiently strong, inhibitory extinction memory of the CS as benign that is unable to outcompete the acquisition memory for activation, as posited by the failure-to-inhibit theory Fig. 1. Schematic display of the competing nature of acquisition (ACQ) and extinction (e.g., Davis et al., 2000). A degree of doubt is cast on the former (EXT) memories of the conditioned stimulus (CS). In this example, ACQ of conditioned mechanism by a strong majority of lab-based conditioning studies fear follows from presentations of the CS together with an electric-shock US during a evidencing normative levels of fear acquisition to the CS in PTSD morning (AM) testing session. The EXT memory is encoded later that afternoon (PM) dur- (e.g., Blechert et al., 2007; Grillon and Morgan, 1999; Milad et al., ing a testing session in which the CS is repeatedly presented in the absence of the US. 2008; Milad et al., 2009; Peri et al., 2000). Such findings suggest These ACQ and EXT learning experiences generate two competing memories of the CS, with the former representing the CS as an anxiogenic predictor of aversive shock and that extinction failure in PTSD, via dominance of the acquisition the latter characterizing the CS as a benign stimulus associated with no aversive outcome. memory over the extinction memory, is unlikely attributable to un- Activation of the ACQ memory of the CS elicits fear, while activation of the EXT memory of duly strong, initial levels of acquisition in patients. That retention the CS elicits no fear. Successful EXT learning depends on an EXT memory of the benign CS of extinction may constitute a more robust marker of PTSD leaves that is strong enough to outcompete the ACQ memory for excitation, thereby inhibiting both activation of the ACQ memory and the associated fear reactivity to the CS. open the possibility for abnormally strong retention of acquisition in patients that, over time, results in acquisition memories too strong for inhibition by extinction memories. Importantly, the absence of 2.1.1. Empirical evidence abnormally strong conditioned responding immediately following Much support for the role of extinction in PTSD is derived from the acquisition among those with PTSD, in the presence of heightened clinical effectiveness of “extinction-like” exposure therapy for the treat- retention of conditioned fear over time, seems consistent with the ment of PTSD (e.g., Rothbaum and Davis, 2003; Rothbaum and Foa, observation that retention of PTSD symptoms, rather than the initial 2002). Specifically, the use of this treatment is predicated on the notion acquisition of such symptoms, distinguishes trauma survivors with, that patients manifest a resistance to extinguish trauma-related fear versus without, PTSD (e.g., Rothbaum and Foa, 1993). Indeed, the that is surmountable through clinical facilitation of the extinction pro- majority of trauma survivors (65%–94%) display posttraumatic cess. Unfortunately, the lab-based evidence is less convincing, with symptoms in the early aftermath of the trauma and only a minority some demonstrating weaker extinction learning in PTSD (e.g., Blechert of survivors meet the diagnostic criteria for PTSD (11%–42%) by et al., 2007; Orr et al., 2000; Wessa and Flor, 2007), but not others retaining such symptoms beyond the first few months post-trauma (e.g., Grillon and Morgan, 1999; Peri et al., 2000). This heterogeneity (estimated percentages from Rothbaum and Foa, 1993). Though in extinction results is difficult to disentangle given the absence of the weight of available data suggests no abnormalities in acquisition methodological or sample characteristics that clearly differentiate of conditioned fear to the conditioned danger cue in PTSD, such data, by studies producing positive versus null findings. For example, findings and large, reflect levels of conditioning during and immediately follow- are inconsistent for: 1) studies assessing extinction psychophysiologi- ing acquisition. Future studies assessing retention of fear to conditioned cally (compare Orr et al., 2000 vs. Peri et al., 2000) or through subjective danger-cues in PTSD are needed before ruling out heightened ratings (compare Wessa and Flor, 2007 vs. Blechert et al., 2007); 2) stud- responding to learned danger-cues as a conditioning marker of PTSD. ies employing electric shock (Orr et al., 2000 vs. Grillon and Morgan, The second mechanism, imputing extinction failure in PTSD to in- 1999) or more mild aversive events (Wessa and Flor, 2007 vs. Peri adequate inhibition of the acquisition memory, has begun to receive et al., 2000) as unconditioned stimuli; and 3) studies testing patients support from results suggesting impaired processes of fear inhibition with combat-related PTSD (Milad et al., 2008 vs. Grillon and Morgan, in PTSD (for a review, see Jovanovic and Ressler, 2010). Because 1999) or non-combat related PTSD (Wessa and Flor, 2007 vs. Bremner these data are directly relevant to both failure-to-extinguish and fail- et al., 2005). One possibility is that extinction deficits relate specifically ure-to-inhibit theories of PTSD, such data will be discussed in the to the re-experiencing cluster of PTSD symptoms (Norrholm et al., context of both models in the Failure to inhibit fear section of this 2011), and that relating extinction deficits to overall levels of PTSD, review. Of note, though Eysenck's incubation version of extinction without considering the severity of individual symptom clusters, frus- theory is appealing on its face, no empirical support for this model trates attempts to link extinction abnormalities to PTSD. in PTSD has been garnered to date. 598 S. Lissek, B. van Meurs / International Journal of Psychophysiology 98 (2015) 594–605

2.2. Associative-learning deficits and sustained contextual anxiety Importantly, this result was accompanied by normative levels of startle potentiation to discrete (non-contextual) cues reliably predicting immi- In dramatic contrast to the conditionability theory of Pitman and col- nent delivery of unpleasant stimulation, specifically linking PTSD to ab- leagues (Orr et al., 2000), the associative-learning-deficits model attri- normal processes of sustained contextual anxiety rather than more butes PTSD to an impaired ability to form aversive associations phasic, discretely-cued, fear responses. Consistently, a prospective through classical conditioning (Grillon, 2002). During a traumatic expe- study of police cadets exposed to police-related trauma, found pre- rience, this deficit is said to prevent the individual from learning envi- trauma levels of subjective anxiety to contextual threat, but not dis- ronmental cues predicting danger. To not know cues for danger is to cretely cued threat, to be predictive of post-trauma symptoms of PTSD be unaware of safety in their absence, leaving the individual in a chronic (Pole et al., 2009). Such results also implicate increased contextual anx- state of anxiety (Seligman and Binik, 1977). Furthermore, the absence of iety as a pre-morbid risk factor for PTSD. threat cues leads the individual to more generally associate the unpleasant US with the environment in which the US is experienced, resulting 2.3. Two-stage learning in heightened contextual anxiety—a form of learning further contributing to chronic anxiety by maintaining diffuse anxiety for the duration A variant of extinction theory, the two-stage learning model views of exposure to the traumatic milieu. Thus chronic anxiety—fueled by avoidance of the CS as the primary force behind extinction failure. both the absence of safety periods and contextual conditioning—is Specifically, classically conditioned fear is proposed to act as a drive viewed as the pathologic consequence of associative-learning deficits that motivates and reinforces avoidance of the CS, thereby denying an in those with, or disposed toward, PTSD (Grillon, 2002). individual the opportunity to extinguish via exposure to the CS in the absence of the US (Eysenck, 1976, 1979; Eysenck and Rachman, 1965; 2.2.1. Empirical evidence Miller, 1948; Mowrer, 1947, 1960). The explanatory power of this Whereas evidence for associative-learning deficits in PTSD is mixed, model is derived largely from its clinical and intuitive appeal. Specifical- with support coming from some studies (Burriss et al., 2008) but not ly, avoidance of learned trauma-cues is central to the clinical presenta- others (Burriss et al., 2007; Geuze et al., 2008; Werner et al., 2009), tion of PTSD, which, by definition, denies patients the exposure the psychopathological endpoint of this model (sustained contextual necessary to extinguish conditioned fear. anxiety) is substantiated by startle-EMG studies evidencing heightened In terms of the competitive-learning model of extinction detailed in contextual anxiety in PTSD. For example, Grillon and Baas (2003) iden- Fig. 1, such avoidance results in an acquisition memory of the CS that re- tify a pattern of results across multiple studies in which heightened ceives no competition from an inhibitory extinction memory, leaving startle magnitudes in PTSD are found in aversive, but not benign, exper- only the memory of the CS as a danger cue available for activation. In imental contexts (for a review see Grillon and Baas, 2003), suggesting our example, the returning veteran may avoid driving or walking on enhanced sensitivity to contextual anxiety among those with PTSD. streets to avert conditioned fear elicited by roadside objects resembling Moreover, a study by Grillon et al. (2009) further examined this link improvised explosive device (IED) encasements encountered during using an instructed threat paradigm designed for within-subject manip- combat. By so doing, the veteran is denied the opportunity to extinguish ulations of contextual danger (Grillon et al., 2004). Specifically, startle this conditioned response, in their now safe post-deployment environ- magnitudes were assessed during three sustained contexts (duration = ment, through exposure to roadside objects in the absence of dangerous 2 min) of increasing aversiveness: 1) a neutral (N) context where no outcomes. unpleasant events were possible; 2) a mildly aversive context where unpleasant stimuli were presented predictably (P); 3) and a more high- 2.3.1. Empirical evidence ly aversive context in which unpleasant stimuli were presented unpre- Although the first classical fear-conditioning stage of this model has dictably (U). The outcome variable was fear-potentiated startle: the received substantial experimentation in PTSD (see above), the extent reliable enhancement of the startle reflex when an organism is in a to which this initial conditioning motivates the second instrumental state of fear (Davis and Astrachan, 1978; Grillon et al., 1991). As can avoidance stage has been the target of little lab-based testing. Indeed, be seen in Fig. 2, fear-potentiated startle to the most aversive context most assessments of avoidance in PTSD have explored correlations (U), relative to the least (N), is significantly stronger in PTSD patients. between PTSD symptom severity and experiential avoidance:theintra- Because this enhanced contextual-potentiation in patients was derived psychic attempt to evade thoughts, emotions, and sensations related from startle responses collected across the 2-minute duration of N, P, to the trauma (e.g., Marx and Sloan, 2005; Simpson et al., 2006). Though and U conditions, such data link PTSD with sustained contextual anxiety. this work has helped elucidate the contribution of mental avoidance to the onset and course of PTSD, it has not allowed for systematic assays of learning mechanisms subserving, the more objectively measurable, behavioral constituents of avoidance in PTSD. Future studies are needed to Neutral assess the way acquisition of lab-based classical fear-conditioning ante- Predictable cedes behavioral avoidance of conditioned stimuli. Our lab is currently -score ) T Unpredictable undertaking such work, and recently validated paradigm demonstrating robust relations between Pavlovian fear-potentiated startle to a CS+ and subsequent behavioral avoidance in the presence of the CS+ (van Meurs et al., 2014). This paradigm will next be applied to test for heightened levels of behavioral avoidance, induced by Pavlovian fear, in those suffering from posttraumatic psychopathology.

Startle -Blink EMG ( 2.4. Over-generalization

Conditioned responses have long been known to transfer, or gener- Fig. 2. Average startle magnitudes in PTSD patients and healthy controls across three levels alize, to stimuli resembling the original CS (Pavlov, 1927). Evidence of contextual aversiveness: 1) neutral context (low threat), during which no unpleasant linking the conditioned generalization process to pathologic anxiety stimulation was delivered, 2) predictable context (moderate threat) during which un- dates back to Watson and Rayner (1920) who famously demonstrated pleasant stimulation was given predictably, and (3) unpredictable context during which ‘ unpleasant stimulation could be given at any time. generalization of conditioned fear to all things fury in a toddler ( Little Adapted from Grillon et al. (2009). Albert’) following acquisition of fear-conditioning to a white rat. This S. Lissek, B. van Meurs / International Journal of Psychophysiology 98 (2015) 594–605 599 kind of conditioned generalization has since been adopted as a core fea- Condioned and Generalizaon Smuli ture of PTSD, through which fear during a traumatic event extends to safe conditions ‘resembling’ the distressing event (American Psychiatric Association, 2013). The pathogenic contribution of conditioned general- CS- GS1 GS2 GS3 GS4 CS+ ization follows from the undue proliferation of trauma cues in the Group 1 individual's environment. That is, generalization results in the spreading of traumatic reactions to stimuli that resemble the CS, but are them- selves benign. Precipitating this proliferation of trauma cues may be an underlying disposition toward reduced thresholds for threat reactivity, resulting in less danger information (i.e., less resemblance to the CS) (A) required for activation of the fear circuit among those with, or prone toward, clinical anxiety (Lissek et al., 2010). The maladaptive effects of this generalization process can be illustrated by an IED exposed combat veteran with PTSD. Though Generalizaon Results conditioned-fear was acquired to a box-shaped encasement of the IED, the veteran's fears may generalize to such other roadside objects in his post-deployment environment as trash cans, ﬁre hydrants, or other 2.0 roadside debris. This may promote frequent trauma-related anxiety in PTSD his benign posttraumatic environment because these roadside objects are ubiquitous in his neighborhood and town. 1.5 Control

2.4.1. Empirical evidence Though generalization of conditioned fear has been featured promi- 1.0 nently in etiologic accounts of maladaptive anxiety at least since Watson and Raynor's (1920) “Little Albert” experiment, lab-based test- 0.5 ing of this idea has been sparse (for a review see Lissek et al., 2008). More recently, this idea has been the target of increased empirical attention, prompted—in part—by meta-analytic results implicating over- 0.0

Perceived Risk for Shock (0-2) CS- GS GS GS GS CS+ generalization of conditioned fear as one of the more robust condition- 1 2 3 4 ing correlates of clinical anxiety generally, and PTSD in particular (Lissek et al., 2005). This result was driven by studies evidencing over- (B) reactivity, among PTSD patients, to safety cues sharing stimulus features (e.g., shape, size, duration, spatial location) with the conditioned danger-cue (e.g., Grillon and Morgan, 1999; Orr et al., 2000; Peri et al., Fig. 3. (A) Conditioned and generalization stimuli included 10 rings of gradually increasing 2000), an effect implying heightened transfer, or generalization, of size with extremes serving as the conditioned danger-cue paired with electric shock (CS+) and the conditioned safety-cue unpaired with shock (CS−). For half of the partic- conditioned fear from the learned danger-cue to resembling stimuli in ipants (Group 1), the largest ring was the CS+ and the smallest was the CS−, and for the PTSD patients. In further pursuit of this finding, our group developed a other half (Group 2) this was reversed. The eight rings of intermediary size served as gen- conditioned fear-generalization paradigm incorporating systematic eralization stimuli (GSs) and created a continuum-of-similarity from CS+ to CS−.Before methods developed and tested in animals (e.g., Armony et al., 1997) analysis, responses to every two intermediaries were collapsed into a single class of in which fear responses are assessed to both the conditioned danger- stimulus, leaving four classes of generalization stimuli (GS1,GS2,GS3,GS4). Collapsing was implemented to avoid an unduly large number of trials while maintaining a gradual cue and generalization stimuli (GSs) parametrically varying in similarity continuum-of-size across rings. Immediately following presentation of each ring, partici- to the danger cue. As in work with animals, such methods applied to pants were asked to rate their perceived risk for receiving a shock on a scale of 0–2 humans yielded generalization gradients, or slopes, with the highest (where 0 = no risk,1=some risk,and2=alotofrisk) to assess the degree to which the level of fear responding to the conditioned danger-cue and gradually conditioned threat value of the CS+ generalized to resembling GSs. (B) Generalization results for 13 adult PTSD patients with mixed traumatic histories (sexual abuse [n =2], decreasing levels of fear generalization to GSs of decreasing similarity physical assault [n =4],caraccident[n =3],other[n = 4]) and 13 age- and sex-matched to the danger cue (Lissek et al., 2008). The steepness of this gradient healthy comparisons indicate less steep gradients of perceived risk in the PTSD group indexes generalization, with less steep downward gradients indicating (group × stimulus-type interaction, p = .003). Though this suggests over-generalization in more generalization. A more detailed description of this method as patients, higher overall risk ratings in PTSD patients (p =.02)implytheadditionalinfluence well as preliminary results, suggesting less steep gradients of generali- of non-associative sensitization on the shape of response gradients in patients. zation in PTSD versus healthy comparisons, can be found in Fig. 3. As illustrated in Fig. 3, findings of less steep gradients of responding in PTSD patients are unlikely due purely to over-generalization of condi- (Kaczkurkin et al., 2013). The triangular control stimulus allows for tioned fear, but rather seem to reflect the combined influence of (asso- the separation of sensitization and generalization processes. Specifical- ciative) generalization and (non-associative) sensitization processes. ly, if PTSD patients over-respond to rings, but not the triangular control Specifically, generalization is evidenced by the downward slope in stimulus, the group difference can be attributed to overgeneralization in PTSD responses as the presented, ring-shaped stimulus increasingly dif- PTSD. If, however, PTSD patients over-respond to both rings and the ferentiates in size from the conditioned danger-cue, and sensitization is triangular control, group differences would be attributable to over- evidenced by the degree to which PTSD responding to most classes of sensitization in PTSD. Results of this recent study demonstrate less ringed stimuli (i.e., GS3,GS2,GS1,&CS−) is elevated relative to healthy steep downward gradients of generalization to ringed stimuli among comparisons. The possibility, however, exists that elevated responding PTSD patients (indicative of over-generalization), in the absence of to most ring sizes in PTSD, seemingly reflecting a sensitization process, over-reactivity to the non-ringed control stimulus. Such results suggest actually stems from conditioned responding that has been generalized overgeneralization rather than over-sensitization as the learning mech- from the ring-shaped danger cue to all ringed stimuli. anism underlying group differences. To date, much of the lab-based This possibility was recently tested in individuals with and without evidence for over-generalization in PTSD has come from our group PTSD using a modified version of this paradigm that includes assess- and the field would benefit from confirmation or disconfirmation of ment of responses to a non-ringed (triangular), control stimulus these findings from other research groups. 600 S. Lissek, B. van Meurs / International Journal of Psychophysiology 98 (2015) 594–605

Clinically, the link between PTSD and overgeneralization prescribes 3. Non-associative fear-learning a therapeutic focus on stimulus events resembling features of the traumatic encounter in addition to the actual features of the encounter. In contrast to fear-conditioning, non-associative fear learning in- Specifically, exposure treatments might focus on reducing fear- volves changes in reactivity to environmental stimuli that are not asso- reactivity to both stimuli associated with the trauma and stimuli ciatively linked to aversive outcomes. In the context of PTSD, non- approximating those associated with the trauma. associative mechanisms are thought to generate increases, or resistance to decreases, in fear reactivity to novel, intense, or fear-relevant stimuli. 2.5. Failure to inhibit fear Contrasting the multiplicity of associative models of PTSD, non- associative accounts largely center on two mechanism of learning: This final associative learning framework links PTSD to impaired habituation and sensitization. mechanisms of fear inhibition, resulting in the expression of fear in the presence of safety cues (Davis et al., 2000; Jovanovic and Ressler, 3.1. Habituation 2010). This model comes as a logical corollary of the above described theory of extinction from Davis et al. (2000) and Jovanovic and Ressler One of the most fundamental and ubiquitous forms of learning is ha- (2010), according to which impaired mechanisms of inhibitory fear- bituation, whereby responding progressively declines with repeated conditioning in PTSD are responsible for extinction-failure. From this stimulation (Groves and Thompson, 1970). In the context of traumatic perspective, all processes dependent on fear-inhibition, including but responding, habituation refers to decreases in autonomic, behavioral, not limited to extinction, should be compromised in PTSD. Safety learn- or neural responses to repeatedly presented novel, intense, or fear- ing in the traumatic context is one such process because cues signaling relevant (unconditioned) stimuli. The failure of this type of habituation periods of safety are effective only if inhibition of ongoing anxiety to the is proposed as a central contributor to the hyper-arousal cluster of PTSD ambient threat of the environment is achieved. This model thus links symptoms (e.g., hyper-vigilance, exaggerated startle, and difficulty con- PTSD to an inability to suppress fear in the presence of safety cues. centrating). For example, hyper-vigilance and exaggerated startle may According to this perspective, our IED exposed veteran who con- be maintained in the benign post-traumatic context through persistent tinues to display conditioned fear to roadside objects, upon return to autonomic responding to reoccurring, and more or less irrelevant, stim- their benign pre-deployment environment, is suffering the effects of uli. Additionally, the inability to filter out these reoccurring sensory failed inhibition of fear in the presence of safety signals. Specifically, stimuli likely compromises concentration by exhausting attentional re- such roadside objects are experienced coincident with many potential sources otherwise available for processing more consequential stimulus environmental cues of safety including neighborhood people, shops, events. parks, and houses associated with, what may have been, the relative safety of his childhood years. Such safety cues are however unable to 3.1.1. Empirical evidence exert inhibitory control over the conditioned response to roadside ob- The failure-to-habituate theory of PTSD receives support from the jects leading to a continuation of the traumatic response in the benign, well replicated finding of less steep habituation slopes to repeatedly civilian context. presented intense acoustic tones in trauma survivors with, versus without, PTSD when assessing habituation with the skin conductance re- 2.5.1. Empirical evidence sponse (SCR: e.g., Orr et al., 1995; Orr et al., 1997; Shalev et al., 1992): Support for the role of deficient fear-inhibition in PTSD-related an index of sympathetic arousal. Indeed, a fairly recent meta-analysis conditioning abnormalities is drawn from neuroimaging data linking identified this SCR habituation effect as the most robust psychophysio- poor retention of extinction in PTSD to an under-functioning medial- logical correlate of PTSD (Pole, 2007). These findings link PTSD to an im- prefrontal cortex (mPFC: Milad et al., 2009): a brain region thought paired ability to autonomically adapt, or habituate, to intense to subserve fear reduction through its demonstrated inhibition of environmental stimuli, and serve as experimental analogues of the amygdaloid neurons (e.g., Quirk et al., 2003; Rosenkranz et al., sustained hyper-arousal and hyper-vigilance seen clinically. Although 2003). Further support for impaired mPFC engagement by fear- such data do not provide clarification on whether decreased SCR habit- inducing stimuli in PTSD, that may instantiate compromised fear in- uation in PTSD precedes or follows the traumatic exposure, a recent hibition, is found by neuroimaging studies documenting reduced prospective study provides support for reduced SCR habituation as a mPFC activation in those with, versus without, PTSD during exposure pre-trauma risk factor for PTSD (Pole et al., 2009). These data are further to traumatic pictures and sounds (Bremner et al., 1999), script driven supported by findings in monozygotic twins documenting strong genet- traumatic imagery (Shin et al., 1999), and fearful faces (Shin et al., ic contributions to rates of SCR habituation, thus supporting SCR habit- 2005; Williams et al., 2006). Additionally, two such studies found in- uation as a premorbid, dispositional trait (Lykken et al., 1988). Unlike verse relations between the severity of PTSD symptomatology and SCR measures of habituation, the weight of habituation effects assessed mPFC responses in PTSD patients (Shin et al., 2005; Williams et al., by heart-rate (HR) and eyeblink-startle responses to intense tones does 2006), supporting the clinical relevance of decreased mPFC engage- not evidence attenuated habituation in PTSD (Pole, 2007). The reason ment during fear evocations. for these differences across measures is unclear, though the presence A final line of work supporting impaired inhibition of fear in PTSD of habituation effects in PTSD when measured with SCR: an index of comes from studies applying a conditional discrimination paradigm sympathetic activation, but not HR: a measure that is sensitive to both (AX+/BX−) designed to assess the degree to which fear to a condi- sympathetic and parasympathetic influences, suggests that reduced tioned danger-cue is reduced when presented in tandem with a condi- habituation in PTSD is attributable to sympathetic abnormalities. tioned safety-cue. Results provide evidence for both decreased inhibition of fear-potentiated startle in the presence of a conditioned 3.2. Sensitization safety-cue (Jovanovic et al., 2010) and less transfer of that inhibition during the combined (configural) presentation of the conditioned The direct inverse of habituation is sensitization: a non-associative danger- and safety-cue, among PTSD patients (Jovanovic et al., 2010, learning mechanism whereby responses are amplified through repeat- 2013). This reduced transfer of inhibition has recently been found to ed stimulation (Groves and Thompson, 1970). In the context of fear predict levels of PTSD in trauma exposed, deployed soldiers 7 months and anxiety, sensitization generally refers to the increase in fear- after testing (Sijbrandij et al., 2013), suggesting that impairments in related responses to novel, intense, or fear-relevant unconditioned fear inhibition may serve as a premorbid risk factor for later develop- stimuli following activation of the fear system (Marks and Tobena, ment of PTSD. 1990). Essentially, fear sensitization is thought to arise from a fear- S. Lissek, B. van Meurs / International Journal of Psychophysiology 98 (2015) 594–605 601 system rendered hyperexcitable by previous activation (Rosen and in PTSD (e.g., Shalev et al., 1992, 1997), though somewhat less robustly Schulkin, 1998). than HR elevations (for a review, see Pole, 2007). Because these psycho- A large body of work in animals has documented stress-related physiological results were largely found in trauma exposed individuals sensitization with some elucidation of its underlying mechanisms. The with versus without PTSD, such findings represent viable support for most common approach involves assessing changes in fear-relevant stronger, trauma-related sensitization of the autonomic nervous system behaviors in rats following exposure to highly stressful conditions. In as a non-associative learning correlate of PTSD. Although it could be ar- one such line of work, defensive responding—operationalized by startle gued that this type of increased HR responding is due to risk factors reactivity to intense bursts of white noise—is reliably enhanced in rats predating the trauma (e.g., genetic predisposition) rather than de after administration of strong electric footshocks (e.g., Davis, 1989). novo learning, both behavioral-genetic data (Orr et al., 2003) and pro- This startle potentiation, referred to as shock sensitization, may model spective assessments (Shalev et al., 2000)characterizethiseffectasan the non-associative hyper-reactivity to intense, novel stimuli seen in acquired (e.g., learned) marker of PTSD rather than a pre-existing risk PTSD, though it is worth noting that the non-associative nature of this factor conferred by heredity or the pre-traumatic environment. effect has been brought into question by evidence imputing shock sen- In contrast to HR findings, enhanced psychophysiological activation sitization to associative fear of the context in which shock was delivered to high intensity acoustic stimuli is not consistently found in PTSD when (for a review, see Richardson and Elsayed, 1998). operationalized by baseline measures of the startle-blink reflex (Grillon A second line of work exposing rats to aversive electric shocks in the and Baas, 2003). The mixed nature of these results is surprising given service of assessing sensitization demonstrates the imperative of stress- that exaggerated startle is a diagnostic feature of PTSD (American Psy- or uncontrollability for displays of stress-related sensitization (for a chiatric Association, 2013). Indeed, findings in rodents and humans re- review, see Maier and Watkins, 2005). Specifically, rats exposed to ines- liably demonstrate the potentiation of startle magnitudes when an capable (uncontrollable) versus escapable (controllable) shocks exhibit organism is in a state of anxious arousal (Davis and Astrachan, 1978; time-limited enhancement (sensitization) of such stress-related pro- Grillon et al., 1991), an emotional state clearly axiomatic to the PTSD di- cesses as avoidance of cat odors (Williams and Groux, 1993), avoidance agnosis. Importantly, a review of this literature reveals an interesting of novel situations and flavors (Job and Barnes, 1995; Minor, 1990), pattern of results whereby elevated baseline startle magnitudes in fear-conditioning (Desiderato and Newman, 1971), suppression of PTSD are found in experimental contexts in which stressful procedures appetitive behaviors (Maier, unpublished data), and avoidance of social ensue (e.g., threat of electric shock), but are not found in contexts rela- interactions (Short and Maier, 1993). Importantly, these effects of tively free of experimental stress (Grillon and Baas, 2003). This dissoci- uncontrollable stress are likely due to non-associative sensitization as ation may best be understood from a kindling perspective on PTSD they occur in contexts with no apparent resemblance to the shock- (e.g., Pittman et al., 1993; Post and Weiss, 1998; Rosen and Schulkin, delivery environment and, as such, are unlikely the result of contextual 1998), according to which psychological trauma sensitizes the fear sys- conditioning. The possibility thus exists that oversensitivity to novel, in- tem among those prone to PTSD, and renders the amygdala-based fear tense, or fear-relevant stimuli of the kind seen in PTSD stems from circuit hyper-excitable to such future fear-evoking situations as stressful trauma-induced stress-sensitization that is dependent on the uncon- experimental contexts. On its face, this conceptualization seems at odds trollable nature of the trauma. The plausibility of this theory is support- with findings of null differences in startle potentiation between survi- ed by the view that the uncontrollable nature of trauma is central to the vors with and without PTSD to instructed, discrete cues signaling immi- etiology of PTSD (e.g., Foa et al., 1992; Volpicelli et al., 1999). nent delivery of aversive stimulation (e.g., Grillon et al., 1998; Grillon One final related animal model induces sensitization through electri- et al., 2009). That is, the kindling model would predict greater trauma- cally stimulating, or partially kindling, the amygdala-based fear circuit related sensitization of the fear circuit in PTSD leaving the circuit with the aim of increasing the excitability of this circuit (for a review, hyper-excitable to threat, and culminating in stronger fear-potentiated see Rosen and Schulkin, 1998).1 limited to only two stimulations and startle to both contextual and discretely-cued signals of danger. This ap- produces no behavioral signs of seizure. Indeed, a number of studies parent inconsistency may be reconciled within the strong situation document increases in fear-related behaviors following amygdala kin- framework (Lissek et al., 2006), whereby strong threats constitute dling in animals (e.g., Adamec and Morgan, 1994). For example, Rosen cues of potent, imminent, and certain danger that evoke the adaptive et al. (1996) found partial kindling (only two stimulations) of the amyg- fear response among anxiety patients and healthy controls alike; and dala to enhance fear-potentiated startle (Rosen et al., 1996). weaker threats constitute cues of less potent, imminent, and certain Additionally, affective consequences of epileptic discharges in the danger to which those with an anxiety disorder are hyper-reactive. human temporal lobe (the cerebral structure encasing the amygdala) In our instance, the situational strength of discrete threat cues is are marked by increases in reported fear and anxiety (e.g., Gloor, stronger than that of contextual threat by virtue of the increased immi- 1978). These findings support the theory that trauma-evoked anxiety nence and certainty of the discretely cued danger. Thus, discrete threat sensitizes the fear system through a partial kindling of the amygdala, cues should elicit a fear response regardless of whether or not the leaving it hyper-reactive to future traumatic encounters, and conferring individual's fear system has been made excitable through stress- risk for PTSD from subsequent trauma. Consistent with this idea are sensitization, and regardless of whether or not the individual has findings demonstrating a heightened incidence of PTSD among those PTSD. By contrast, such weak situations as contextual threat may elicit with previous histories of trauma-exposure (e.g., Bremner et al., 1993; fear only in individuals for whom hyper-excitability of the fear system Breslau et al., 1999; Davidson et al., 1991). was achieved through sensitization (e.g., PTSD patients), with all others experiencing only sub-threshold levels of fear activation. Increased baseline startle in stressful contexts found in PTSD, therefore, supports 3.2.1. Empirical evidence a role for sensitization via kindling in the disorder, despite null Perhaps the strongest evidence for greater sensitization of fear- patient–control differences in startle potentiation to discrete threat related autonomic responses in PTSD, is psychophysiology studies cues. assessing HR responses to repeatedly presented, high intensity acoustic Further findings consistent with the kindling model of PTSD are stimuli, the majority of which document larger average HR responses in derived from neuroimaging studies tracking the neural correlates of PTSD patients (e.g., Carson et al., 2007; Jovanovic et al., 2009; Metzger fearful-face processing across those with and without PTSD. Presenta- et al., 1999; Orr et al., 1995, 1997, 2003; Shalev et al., 1992, 2000). Sev- tions of fearful facial expressions reliably activate the human amygdala eral studies have also found stronger SCR to these same acoustic stimuli (e.g., Hariri et al., 2003; Morris et al., 1996; Phillips et al., 1997), and have become a noninvasive means of probing amygdala function in 1 Full kindling produces seizures in the activated tissue while partial kindling is usually. the intact human brain. If, as held by the kindling model, trauma- 602 S. Lissek, B. van Meurs / International Journal of Psychophysiology 98 (2015) 594–605 evoked fear renders the amygdala-based fear circuit hyper-excitable in and safety cues resembling threat cues (to which fear generalizes) survivors who develop PTSD, post-traumatic presentations of fearful may be thought to constitute weaker threats. That is, compared to dis- faces should produce stronger amygdala reactions in those with PTSD. crete conditioned danger cues, contextual threat communicates danger Several studies confirm this prediction with fearful faces (vs. happy of less imminence; unpredictable threat signals danger of less certainty; faces) evoking stronger amygdala reactions in trauma survivors with and cues approximating the likeness of the danger cue constitute PTSD compared to those without PTSD (e.g., Rauch et al., 2000; Shin threats of greater ambiguity. Consistent with predictions of the strong et al., 2005; Felmingham et al., 2010). Additional findings of amygdala situation framework, PTSD–control differences in anxious reactivity hyper-excitability to neutral faces in those with versus without PTSD have not been reliably found to the stronger discrete conditioned danger indicate that the effect may not be restricted to ‘fearful’ faces (Brunetti cue and seem to emerge under weaker situations of contextual threat et al., 2010). It should be noted that the increased amygdala reactivity (e.g., Grillon and Baas, 2003), unpredictable threat (Grillon et al., in PTSD may reflect a premorbid risk factor rather than abnormal stress 2009), and perceptually degraded danger cues (Kaczkurkin et al., sensitization of this circuit; prospective research on amygdala responses 2013). Although this framework does not thoroughly account for the to faces in PTSD is needed to clarify this issue. rich variety of findings in this literature, it may help set the stage for The above described experimental support for the sensitization-by- future, more comprehensive, integrative explanations. kindling hypothesis of PTSD is well complimented by phenomenologi- cal data revealing greater risk for PTSD among survivors with a history 5. Research limitations and future directions of previous traumatic exposures (e.g., Breslau et al., 1999; Brewin et al., 2000; Ozer et al., 2003). These findings suggest that psychological The past two decades have seen substantial increases in lab-based trauma kindles the fear-system, and renders it maladaptively hyper- testing of associative and non-associative learning abnormalities in reactive to future trauma. PTSD. Although tests of extinction failure in PTSD are well represented The final sensitization theory reviewed herein imputes non- in this recent literature, the variety of other promising learning theories associative learning correlates of PTSD to the uncontrollable nature of of PTSD detailed herein have, to date, received relatively little empirical the stressor (trauma). This theory of PTSD has received little experimen- attention. Indeed, PTSD abnormalities in contextual anxiety, condi- tal testing, which is unfortunate given the general view that uncontrol- tioned generalization, and failure to inhibit fear to safety cues have lability and unpredictability are critical features of PTSD-inducing each, more or less, been completed by single laboratories, and the events (e.g., Foa et al., 1992; Mineka and Zinbarg, 2006; Volpicelli field awaits replication of these findings by other laboratories. Addition- et al., 1999). This general view stems largely from animal data ally, the vast majority of conditioning studies in PTSD have targeted pro- documenting behavioral consequences of uncontrollable and unpre- cesses of Pavlovian fear-conditioning (extinction, over-generalization, dictable threats that are analogous to many symptoms of PTSD (for a etc.) and have not tested abnormalities in instrumental fear- review, see Foa et al., 1992). Non-experimental evidence for this per- conditioning (i.e., learned avoidance). This is a significant omission, spective is derived from studies documenting inverse relations between given the centrality of conditioned avoidance of trauma reminders to perceptions of control and PTSD symptoms among survivors of sexual posttraumatic psychopathology (American Psychiatric Association, victimization (Bolstad and Zinbarg, 1997; Regehr et al., 1999) and crim- 2013). In fact, some evidence from clinical research implicates avoid- inal assault (Kushner et al., 1993). Extant experimental support comes ance as the class of symptoms most detrimental to psychosocial func- from initiatives testing the relation between clinical anxiety and threat tioning in trauma survivors (Hendrix et al., 1998; Samper et al., 2004; predictability (e.g., Grillon et al., 2008), which is a characteristic of Solomon and Mikulincer, 2007), and may predict posttraumatic psycho- threat distinct from, but highly related to, controllability. In a recent pathology better than other trauma-related symptom clusters (Bryant study conducted by Grillon et al. (2009), PTSD patients displayed et al., 2000; North et al., 1999; North et al., 2012). normative levels of fear-potentiated startle to threat cues signaling In addition to this problem of investigative scope, existing studies imminent aversive noises (e.g., predictable threat), but elevated fear- often identify PTSD-related learning abnormalities that are not unam- potentiated startle during a sustained period in which aversive biguously attributable to a single learning mechanism. For example, noises were delivered at random (i.e., unpredictable threat). These over-responding to the conditioned safety cue (CS−) repeatedly findings demonstrate a heightened reactivity to threat-unpredictability found in PTSD patients, could reflect over-responding to all novel cues in PTSD, and provide a degree of support for the hypothesis that uncon- (i.e., sensitization), heightened transfer of responding to cues resem- trollable/unpredictable threat differentially sensitizes the fear system of bling the CS+ (overgeneralization), an impaired ability to accurately those with, versus without, PTSD. learn the link between the CS+ and US (associative learning deficits) or failure to inhibit fear to safety cues. Additionally, resistance to extin- 4. Toward an integrated account of learning findings in PTSD guish fear could reflect overly strong excitation learning to the CS+ at acquisition, or too little learned fear inhibition to the CS+ at extinction. Studies reviewed thus far report a variety of results across a multi- Some of these interpretive problems can be addressed by way of im- plicity of stress-related learning mechanisms with proposed relevance proved experimental design. For example, further tests of over- to PTSD. Although no unified conceptualization of these results is readily reactivity to the CS− in PTSD would benefit from use of generalization obvious, the social psychological concept of the strong situation may methods in which fear responding is assessed to CS− that are perceptu- provide an interpretive framework with which to deduce the begin- ally similar and dissimilar to the CS+. That is, over-responding in PTSD nings of a unified account. As described previously, the strong threat patients to perceptually similar but not dissimilar CS− reflects an over- situation represents an experimental condition that unambiguously sig- generalization process rather than a general over-responding to either nals aversive events of high certainty and imminence, and evokes the all CS− (as predicted by the failure-to-inhibit hypothesis) or all novel adaptive fear response among anxiety patients and healthy controls stimuli (as predicted by the sensitization hypothesis). alike. Weakening the experimental situation by reducing the temporal Other efforts to link specific learning abnormalities to PTSD may proximity of the stressor, decreasing the predictive value of the danger benefit from brain imaging techniques. For example, the contributions cue, and/or increasing the ambiguity of the threat information is of fear excitation versus fear inhibition processes toward extinction ab- predicted to facilitate the emergence of patient–control differences in normalities in PTSD may be dissociated by the specificbraincorrelates anxious reactivity. of these abnormalities, with perturbed activation in areas attributed to In our context, the discrete conditioned danger cue is something of a fear excitation (e.g., amygdala, anterior insula) implicating excitatory strong situation by virtue of its relatively unambiguous signaling of abnormalities and perturbations in brain areas associated with fear inhi- certain and imminent danger. Contextual threat, unpredictable threat, bition (e.g., ventromedial prefrontal cortex) suggestive of inhibitory S. Lissek, B. van Meurs / International Journal of Psychophysiology 98 (2015) 594–605 603 abnormalities. This approach has begun to yield fruit, with brain imag- survivors of comparable traumas is evidence of gene by environment in- ing results attributing deficiencies in extinction recall to perturbations teractions. As such, modern learning theories of PTSD must account for in circuitry associated with fear inhibition (e.g., Milad et al., 2009). the genetic liabilities that dispose some trauma survivors to maladap- Once methodologies for isolating specific learning abnormalities are tive learning following traumatic encounters. Though this effort is un- identified or developed, the field would benefit from studies designed to derway (for a review see Amstadter et al., 2009), more work of this assess multiple learning mechanisms in samples of traumatic stress kind is needed. patients large enough to distinguish different types of learning abnor- A final limitation of this literature lies in the inability of learning malities in different clusters of patients. Because it is likely different models to account for the full richness of PTSD phenomenology. Though that learning mechanisms (e.g., sensitization, extinction failure, gener- associative and non-associative learning abnormalities are well posi- alization, contextual anxiety) contribute differently to PTSD across dif- tioned to account for a subset of PTSD symptoms (re-experiencing, ferent individuals, it would be useful to identify subclasses of PTSD avoidance, hyper-arousal), they do not seem particularly well suited patients affected by different mechanisms alone or in combination. to explain the full clinical picture of PTSD, including symptoms related Targeting a single learning mechanism putatively associated with to guilt, shame, dissociation, and anger. Future learning research should PTSD, as done by the majority of extant studies, may underestimate assess the relatedness of learning abnormalities to these other types of learning effects in PTSD by capturing learning aberrancies in only the symptoms. Though learning mechanisms will probably not provide a subset of PTSD patients displaying abnormalities in the particularly full explanation of such symptoms, important interactions may emerge. targeted learning mechanism, and missing individuals with abnormalities in other learning processes. 6. Summary and concluding thoughts An additional limitation of this literature that besets much of experimental psychopathology is whether abnormalities in patients generat- A rich array of learning-based theories of PTSD have emerged during ed by lab-based testing reflect pre-morbid risk factors or ongoing the century following Watson and Rayner's (1920) seminal experiment disease processes. The dissociation of the former from the latter is facil- on “Little Albert”. Such learning models have offered mechanized ac- itated by prospective data relating pre-morbid to post-morbid findings, counts of PTSD based on basic learning processes that are readily probed as well as behavioral genetic methods designed to disentangle the influ- and objectively quantified in the laboratory environment. It is thus sur- ence of genetic risk from that of environment, on onset and mainte- prising that empirical testing of these models has occurred primarily in nance of the disorder. The available data of this type in the PTSD the most recent two decades. During this time, evidence for a variety of literature on learning abnormalities characterizes effects of poor recall PTSD-related abnormalities in basic learning processes have been of extinction and over-sensitization as acquired markers of PTSD found, the most promising of which include slowed habituation of (Milad et al., 2008; Orr et al., 2003; Shalev et al., 2000), and deficits in skin conductance responses (SCRs) to intense environmental stimuli, original extinction learning (Guthrie and Bryant, 2006; Lommen et al., heightened sensitization of heart-rate responses to loud acoustic noises, 2013), enhanced contextual anxiety (Pole et al., 2009)anddeficient failure to retain extinction learning as indicated by increased SCRs and habituation (Pole et al., 2009) as pre-trauma risk factors for PTSD. reduced activation in brain areas associated with fear inhibition during Nevertheless, more data is needed before conclusions can be drawn, exposure to the previously extinguished CS+, overgeneralization of with confidence, regarding the value of a given learning abnormality conditioned fear as indicated by elevated perceptions of shock risk to as a vulnerability factor for, versus a diagnostic marker of, PTSD. One for- stimuli resembling the CS+, heightened contextual anxiety as indicated tuitous consequence of the cross-species relevance of associative and by larger fear-potentiated startle during experimental conditions of un- non-associative learning processes implicated in the etiology of PTSD predictable threat, and deficits inhibiting fear to safety cues as indicated is the availability of rich neuroscience findings in animals from which by reduced suppression of fear-potentiated startle in the presence of to generate and test psychobiological accounts of PTSD. For example, safety cues. Importantly, the cross-species relevance of such learning data in animals suggests that sensitization-like PTSD symptoms in the processes brings to bear a wealth of animal data from which to infer hyper-arousal cluster are, in part, instantiated by the activation of a the neural basis of these PTSD-related learning abnormalities. This subset of serotonergic neurons in the dorsal raphe nucleus (DRN) translational bridge between animal and PTSD findings promises to projecting to the basolateral amygdala during uncontrollable stress contribute essentially to the field's dedicated efforts toward future (for a review, see Maier and Watkins, 2005). Additionally, fear- brain-based diagnostics and neurally-targeted interventions for PTSD. conditioning research in animals employing lesion and single-cell- recording methods have linked extinction and its retention to the References vmPFC (e.g., Milad and Quirk, 2002; Quirk et al., 2000), which is a brain region strongly implicated in fear reduction through inhibitory Adamec, R.E., Morgan, H.D., 1994. The effect of kindling of different nuclei in the left and – fl right amygdala on anxiety in the rat. Physiol. Behav. 55, 1 12. in uences on the amygdala (Quirk et al., 2003; Rosenkranz et al., American Psychiatric Association, 2013. 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