Updating versus Exposure to Prevent Consolidation of Conditioned Fear.
ABSTRACT: Targeting the consolidation of fear memories following trauma may offer a promising method for preventing the development of flashbacks and other unwanted re-experiencing symptoms that characterise Posttraumatic Stress Disorder (PTSD). Research has demonstrated that performing visuo-spatial tasks after analogue trauma can block the consolidation of fear memory and reduce the frequency of flashbacks. However, no research has yet used verbal techniques to alter memories during the consolidation window. This is surprising given that the most effective treatments for PTSD are verbally-based with exposure therapy and trauma-focused cognitive behavioural therapy gaining the most evidence of efficacy. Psychological therapies aim to reduce the conditioned fear response, which is in keeping with the preliminary finding that an increased propensity for fear conditioning may be a vulnerability factor for PTSD. Our research had two aims. We investigated the degree to which individual differences in fear conditioning predict the development of PTSD symptoms. We also compared the preventative effects of two clinically informed psychological techniques administered during the consolidation window: exposure to the trauma memory and updating the meaning of the trauma. 115 healthy participants underwent a fear conditioning paradigm in which traumatic film stimuli (unconditioned stimuli) were paired with neutral stimuli (conditioned stimuli). Participants were randomly allocated to an updating, exposure or control group to compare the effects on the conditioned fear response and on PTSD symptomatology. The results showed that stronger conditioned responses at acquisition significantly predicted the development of PTSD symptoms. The updating group, who verbally devalued the unconditioned stimulus within the consolidation window, experienced significantly lower levels of PTSD symptoms during follow-up than the exposure and control groups. These findings are consistent with clinical interventions for chronic PTSD and have important implications for identifying those at risk as well as for designing novel early interventions to prevent the development of PTSD.
Project description:Fear conditioning is an established model for investigating posttraumatic stress disorder (PTSD). However, symptom triggers may vaguely resemble the initial traumatic event, differing on a variety of sensory and affective dimensions. We extended the fear-conditioning model to assess generalization of conditioned fear on fear processing neurocircuitry in PTSD. Military veterans (n=67) consisting of PTSD (n=32) and trauma-exposed comparison (n=35) groups underwent functional magnetic resonance imaging during fear conditioning to a low fear-expressing face while a neutral face was explicitly unreinforced. Stimuli that varied along a neutral-to-fearful continuum were presented before conditioning to assess baseline responses, and after conditioning to assess experience-dependent changes in neural activity. Compared with trauma-exposed controls, PTSD patients exhibited greater post-study memory distortion of the fear-conditioned stimulus toward the stimulus expressing the highest fear intensity. PTSD patients exhibited biased neural activation toward high-intensity stimuli in fusiform gyrus (P<0.02), insula (P<0.001), primary visual cortex (P<0.05), locus coeruleus (P<0.04), thalamus (P<0.01), and at the trend level in inferior frontal gyrus (P=0.07). All regions except fusiform were moderated by childhood trauma. Amygdala-calcarine (P=0.01) and amygdala-thalamus (P=0.06) functional connectivity selectively increased in PTSD patients for high-intensity stimuli after conditioning. In contrast, amygdala-ventromedial prefrontal cortex (P=0.04) connectivity selectively increased in trauma-exposed controls compared with PTSD patients for low-intensity stimuli after conditioning, representing safety learning. In summary, fear generalization in PTSD is biased toward stimuli with higher emotional intensity than the original conditioned-fear stimulus. Functional brain differences provide a putative neurobiological model for fear generalization whereby PTSD symptoms are triggered by threat cues that merely resemble the index trauma.
Project description:OBJECTIVE:Heightened generalization of fear from an aversively reinforced conditioned stimulus (CS+, a conditioned danger cue) to resembling stimuli is widely accepted as a pathogenic marker of posttraumatic stress disorder (PTSD). Indeed, a distress response to benign stimuli that "resemble" aspects of the trauma is a central feature of the disorder. To date, the link between overgeneralization of conditioned fear and PTSD derives largely from clinical observations, with limited empirical work on the subject. This represents the first effort to examine behavioral and brain indices of generalized conditioned fear in PTSD using systematic methods developed in animals known as generalization gradients: the gradual decline in conditioned responding as the presented stimulus gradually differentiates from CS+. METHOD:Gradients of conditioned fear generalization were assessed using functional MRI and behavioral measures in U.S. combat veterans who served in Iraq or Afghanistan and had PTSD (N=26), subthreshold PTSD (N=19), or no PTSD (referred to as trauma control subjects) (N=17). Presented stimuli included rings of graded size, with extreme sizes serving as CS+ (paired with shock) and as a nonreinforced conditioned stimulus (CS-, a conditioned safety cue), and with intermediate sizes forming a continuum of similarity between CS+ and CS-. Generalization gradients were assessed as response slopes from CS+, through intermediate ring sizes, to CS-, with less steep slopes indicative of stronger generalization. RESULTS:Relative to trauma control subjects, PTSD patients showed stronger conditioned generalization, as evidenced by less steep generalization gradients in both behavioral risk ratings and brain responses in the left and right anterior insula, left ventral hippocampus, dorsolateral and dorsomedial prefrontal cortex, and caudate nucleus. Severity of PTSD symptoms across the three study groups was positively correlated with levels of generalization at two such loci: the right anterior insula and left ventral hippocampus. CONCLUSIONS:The results point to evidence of brain-based markers of overgeneralized fear conditioning related to PTSD. These findings provide further understanding of a central yet understudied symptom of trauma-related psychopathology.
Project description:Intrusive memories--a hallmark symptom of posttraumatic stress disorder (PTSD)--are often triggered by stimuli possessing similarity with cues that predicted or accompanied the traumatic event. According to learning theories, intrusive memories can be seen as a conditioned response to trauma reminders. However, direct laboratory evidence for the link between fear conditionability and intrusive memories is missing. Furthermore, fear conditioning studies have predominantly relied on standardized aversive stimuli (e.g. electric stimulation) that bear little resemblance to typical traumatic events. To investigate the general relationship between fear conditionability and aversive memories, we tested 66 mentally healthy females in a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with neutral sounds as conditioned stimuli and short violent film clips as unconditioned stimuli. Subsequent aversive memories were assessed through a memory triggering task (within 30 minutes, in the laboratory) and ambulatory assessment (involuntary aversive memories in the 2 days following the experiment). Skin conductance responses and subjective ratings demonstrated successful differential conditioning indicating that naturalistic aversive film stimuli can be used in a fear conditioning experiment. Furthermore, aversive memories were elicited in response to the conditioned stimuli during the memory triggering task and also occurred in the 2 days following the experiment. Importantly, participants who displayed higher conditionability showed more aversive memories during the memory triggering task and during ambulatory assessment. This suggests that fear conditioning constitutes an important source of persistent aversive memories. Implications for PTSD and its treatment are discussed.
Project description:Posttraumatic stress disorder (PTSD) can be conceptualized as a disorder of emotional memory showing strong (conditioned) responses to trauma reminders and intrusive memories among other symptoms. Women are at greater risk of developing PTSD than men. Recent studies have demonstrated an influence of ovarian steroid hormones in both fear conditioning and intrusive memory paradigms. However, although intrusive memories are considered non-extinguished emotional reactions to trauma reminders, none of the previous studies has investigated effects of ovarian hormones on fear conditioning mechanisms and intrusive memories in conjunction. This may have contributed to an overall inconsistent picture of the role of these hormones in emotional learning and memory. To remedy this, we exposed 37 healthy women with a natural menstrual cycle (during early follicular or luteal cycle phase) to a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with short violent film clips as unconditioned stimuli. Intrusive memories about the film clips were assessed ambulatorily on subsequent days. Women with lower levels of estradiol displayed elevated differential conditioned skin conductance responding during fear extinction and showed stronger intrusive memories. The inverse relationship between estradiol and intrusive memories was at least partially accounted for by the conditioned responding observed during fear extinction. Progesterone levels were not associated with either fear acquisition/extinction or with intrusive memories. This suggests that lower levels of estradiol might promote stronger symptoms of PTSD through associative processes.
Project description:Oxytocin reportedly decreases anxious feelings in humans and may therefore have therapeutic value for anxiety disorders, such as post-traumatic stress disorder (PTSD). As PTSD patients have exaggerated startle responses, a fear-potentiated startle paradigm in rats may have face validity as an animal model to examine the efficacy of oxytocin in treating these symptoms. Oxytocin (0, 0.01, 0.1, or 1.0 μg, subcutaneously) was given either 30 min before fear conditioning, immediately after fear conditioning, or 30 min before fear-potentiated startle testing to assess its effects on acquisition, consolidation, and expression of conditioned fear, respectively. Startle both in the presence and absence of the fear-conditioned light was significantly diminished by oxytocin when administered at acquisition, consolidation, or expression. There was no specific effect of oxytocin on light fear-potentiated startle. In an additional experiment, oxytocin had no effects on acoustic startle without previous fear conditioning. Further, in a context-conditioned test, previous light-shock fear conditioning did not increase acoustic startle during testing when the fear-conditioned light was not presented. The data suggest that oxytocin did not diminish cue-specific conditioned nor contextually conditioned fear, but reduced background anxiety. This suggests that oxytocin has unique effects of decreasing background anxiety without affecting learning and memory of a specific traumatic event. Oxytocin may have antianxiety properties that are particularly germane to the hyper-vigilance and exaggerated startle typically seen in PTSD patients.
Project description:One key conditioning abnormality in posttraumatic stress disorder (PTSD) is heightened generalization of fear from a conditioned danger-cue (CS+) to similarly appearing safe stimuli. The present work represents the first effort to track the time-course of heightened generalization in PTSD with the prediction of heightened PTSD-related over-generalization in earlier but not later trials. This prediction derives from past discriminative fear-conditioning studies providing incidental evidence that over-generalization in PTSD may be reduced with sufficient learning trials. In the current study, we re-analyzed previously published conditioned fear-generalization data (Kaczkurkin et al., 2017) including combat veterans with PTSD (n?=?15) or subthreshold PTSD (SubPTSD: n?=?18), and trauma controls (TC: n = 19). This re-analysis aimed to identify the trial-by-trial course of group differences in generalized perceived risk across three classes of safe generalization stimuli (GSs) parametrically varying in similarity to a CS+ paired with shock. Those with PTSD and SubPTSD, relative to TC, displayed significantly elevated generalization to all GSs combined in early but not late generalization trials. Additionally, over-generalization in PTSD and SubPTSD persisted across trials to a greater extent for classes of GSs bearing higher resemblance to CS+. Such results suggest that PTSD-related over-generalization of conditioned threat expectancies can be reduced with sufficient exposure to unreinforced GSs and accentuate the importance of analyzing trial-by-trial changes when assessing over-generalization in clinical populations.
Project description:In basic research, the etiology of fear-related pathologies, such as post-traumatic stress disorder (PTSD), is conceptualized using fear-conditioning protocols that pair environmental stimuli (that is, a conditioned stimulus-CS) with an aversive, unconditioned stimulus (US) to elicit an assessable conditioned fear response. Although pathophysiological models agree that regulatory dysfunctions in this associative process may instigate fear-related pathology, current opinions differ in regard to the nature of these dysfunctions. Primarily derived from studies in rodents, the prevailing perspective proposes that pathological fear-reactions develop from intensified and overly consolidated CS-US associations. Alternatively, models derived from studies in humans suggest that tempospatial inaccuracies in representations of associative fear might precipitate pathology by engendering failure to differentiate present experiences and past memories of threat. To test this concept in rodents, we administered rats with cognition enhancing doses of Methylphenidate before or after fear conditioning and measured long-term alterations in their conditioned fear behaviors and PTSD-like reactions. The administration of Methylphenidate before fear-memory formation indeed reduced anxious-like responses during fear-memory retrieval one month later. An individual profiling analysis revealed that Methylphenidate onset had opposing effects on the risk for PTSD-like classification. The modulation of initial learning and formation of associative fear normalized the risk for developing PTSD-like reaction. In contrast, when the effects of Methylphenidate were exerted only over later consolidation this risk increased markedly. When examined under current psychiatric and neuropharmacologic literature, these results reveal a possible strategy of using low-dose Methylphenidate for the prevention of PTSD in high risk populations.
Project description:Cortisol is a stress hormone and potent modulator of learning and memory processes. If administered after learning, cortisol can enhance memory consolidation. Yet it is unknown whether cortisol administration after fear extinction learning strengthens extinction memory. Extinction is a crucial mechanism underlying psychotherapy of posttraumatic stress disorder (PTSD). The present study examined whether extinction can be enhanced by administering cortisol after extinction training. In a registered, randomized, double-blind and placebo controlled trial, 50 healthy participants were exposed to a differential fear-conditioning paradigm with neutral faces as conditioned stimuli (CS) and traumatic film clips as unconditioned stimuli (US). They received either cortisol (n = 25) or placebo (n = 25) immediately after extinction. The cortisol group showed less fear during a return of fear manipulation (reinstatement) evidenced by attenuated fear potentiated startle responses and US-expectancy ratings than the placebo group. Results indicate that cortisol administration after fear extinction strengthens extinction memory and suggest that it might be advantageous to administer cortisol subsequent to successful exposure treatment sessions.
Project description:The symptoms of posttraumatic stress disorder (PTSD) can be explained, at least in part, as an inability to inhibit learned fear during conditions of safety. Our group has shown that fear inhibition is impaired in both combat and civilian PTSD populations. On the basis of our earlier findings, we employed an established fear extinction paradigm to further explore fear dysregulation in a civilian traumatized population.Fear-potentiated startle (FPS) was examined in 127 trauma-exposed individuals with and without PTSD. We used a protocol in which conditioned fear was first acquired through the presentation of one colored shape (reinforced conditioned stimulus, [CS+]) that was paired with an aversive air blast to the larynx (unconditioned stimulus) and a different colored shape that was not paired to the air blast (nonreinforced condition stimulus). Fear was extinguished 10 min later through repeated presentations of the CSs without reinforcement.Both groups demonstrated successful fear conditioning on the basis of startle and unconditioned stimulus-expectancy ratings; however, participants with PTSD displayed greater FPS responses to the CS+ and nonreinforced conditioned stimulus compared with the group without PTSD. During fear extinction, the PTSD group showed elevated FPS responses to the previously reinforced CS+ during the early and middle stages of extinction. During the acquisition and extinction phases, PTSD participants with higher levels of reexperiencing symptoms exhibited greater potentiated startle responses to the CS+ compared with PTSD participants with lower reexperiencing symptoms.These results suggest that PTSD is associated with enhanced fear learning and a greater "fear load" to extinguish after conditioned fear is acquired.
Project description:BACKGROUND:Fear-based disorders, like social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD), are characterized by an exaggerated fear response and avoidance to trigger cues, suggesting a transdiagnostic mechanism of psychopathology. Current theories suggest that abnormalities in conditioned fear is a primary contributor to the pathophysiology of these disorders. The primary goal of this study was to compare acquisition of conditioned stimulus (CS) and aversive unconditioned stimulus (US) contingencies during fear learning and extinction in individuals with SAD and PTSD. METHODS:In a standard Pavlovian fear conditioning-extinction paradigm we measured subjective US expectancy ratings to different CSs in patients with SAD (n=16) compared to patients with PTSD (n=13) and healthy controls (n=15) RESULTS: Both patient groups (SAD, PTSD) acquired differential conditioning between a CS that predicted US (CS+) and a CS that never predicted the US (CS-), however, both groups reported an increased expectancy that the US would occur following the CS-. Additionally, the PTSD group overestimated that the US would occur in general. Neither patient group showed evidence of successful extinction of the CS+-US contingency nor differentiated their expectation of US occurrence between the CS+ and CS- during extinction learning. LIMITATIONS:Group sample sizes were small and we did not include a trauma-exposed group without PTSD CONCLUSIONS: Both SAD and PTSD generalize expectations of an aversive outcome across CSs, even when a CS never signals an aversive outcome and PTSD may tend to over-expect threat. Fear learning and extinction abnormalities may be a core feature underlying shared symptoms across fear-based disorders.