Generalization Of Conditioned Fear Research Articles

The Impact of Continuous and Partial Reinforcement on the Acquisition and Generalization of Human-Conditioned Fear

Fear over-generalization as a core symptom of anxiety disorders is manifested by fear responses even to safe stimuli that are very dissimilar to the original dangerous stimulus. The present study investigated the effects of two separate conditioned stimuli–unconditioned stimuli (CS–US) pairing procedures on fear acquisition and generalization using a perceptual discrimination fear-conditioning paradigm, with US expectancy ratings and skin conductance response (SCR) as indicators. One group accepted continuous followed by partial CS–US pairings (C–P group); the other group accepted partial followed by continuous CS–US pairings (P–C group). It was found that compared to the P–C group, the C–P group showed stronger perceptual discrimination of CS+ and CS− in the fear acquisition and showed weaker SCRs and stronger extinction of US expectancy in the generalization. These findings emphasize that CS–US pairings significantly influence fear acquisition and generalization and suggest that continuous-following partial CS–US pairings promote individual discrimination of threat and safety signals and inhibit the generalization of conditioned fear. The results of this study have implications for clinical interventions for patients experiencing negative events.

Understanding clinical fear and anxiety through the lens of human fear conditioning.

Fear is an adaptive emotion that mobilizes defensive resources upon confrontation with danger. However, fear becomes maladaptive and can give rise to the development of clinical anxiety when it exceeds the degree of threat, generalizes broadly across stimuli and contexts, persists after the danger is gone or promotes excessive avoidance behaviour. Pavlovian fear conditioning has been the prime research instrument that has led to substantial progress in understanding the multi-faceted psychological and neurobiological mechanisms of fear in past decades. In this Perspective, we suggest that fruitful use of Pavlovian fear conditioning as a laboratory model of clinical anxiety requires moving beyond the study of fear acquisition to associated fear conditioning phenomena: fear extinction, generalization of conditioned fear and fearful avoidance. Understanding individual differences in each of these phenomena, not only in isolation but also in how they interact, will further strengthen the external validity of the fear conditioning model as a tool with which to study maladaptive fear as it manifests in clinical anxiety.

Reversing threat contingencies enhances generalization of conditioned fear

Generalization of conditioned fear to stimuli resembling a conditioned danger-cue (CS+) is proposed as a key mechanism of clinical anxiety. Given that threat contingencies can be ever changing in day-to-day life, the impact of such changes on generalization is critical to understanding how generalization manifests in the lives of those with and without clinical anxiety. Here, we add a reversal of threat contingency manipulation to a well validated fear-generalization paradigm to provide the first assessment of reversal effects on generalized conditioned fear. Healthy adult participants were presented rings of increasing size, with extreme sizes serving as CS+ (paired with electric shock) and CS- (never paired), and intermediate sizes serving as generalization stimuli (GS) that formed a continuum-of-similarity between CS+ and CS-. An acquisition phase including CS+ and CS- presentations was followed by a generalization test including presentations of each ring sizes (CS+, GSs, CS-). One group of participants (n = 26) received a CS+/CS- reversal instruction prior to generalization, while a second group (n = 29) received no such instruction. Though comparable levels of discriminative conditioning to CS+ versus CS- were found across groups, the reversal group displayed greater generalization of both perceived threat and fear-potentiated startle relative to the no reversal group. Such results indicate a generalization-enhancing effect of reversing threat contingencies and highlight the importance of future work studying the clinical relevance of this effect.

The effect of partial and continuous reinforcement on the generalization of conditioned fear in humans

The popular paradigm of Pavlovian conditioned fear has been used to study learning and memory processes that mediate anxiety disorder. Fear extinction studies have often paired the conditioned stimulus (CS) and the unconditioned stimulus (US) on a subset of acquisition trials (partial reinforcement) to prolong extinction. However, there have been few studies on the effect of partial reinforcement and continuous reinforcement on fear generalization. To better understand the influence of the CS–US pairing rate on fear generalization, the experimenters used CSs paired with US at 50% (CS50), 75% (CS75), and 100% (CS100) during fear conditioning. A total of 66 participants, who were assigned at random to the different reinforcement rates, underwent fear acquisition and generalization tests on expectancy ratings and skin conductance responses. The continuous reinforcement group (CS100) showed a flatter generalization gradient, while the partial reinforcement groups (CS50, CS75) showed increased generalization magnitudes. These results suggest that the partial reinforcement extinction effect is related to threat intensity, whereas continuous reinforcement produces threat-sensitivity fear generalization, which has been used to explain the overgeneralization of fear.

A meta-analysis of conditioned fear generalization in anxiety-related disorders.

Generalization of conditioned fear is adaptive in some situations but maladaptive when fear excessively generalizes to innocuous stimuli with incidental resemblance to a genuine threat cue. Recently, empirical interest in fear generalization as a transdiagnostic explanatory mechanism underlying anxiety-related disorders has accelerated. As there are now several studies of fear generalization across multiple types of anxiety-related disorders, the authors conducted a meta-analysis of studies reporting behavioral measures (subjective ratings and psychophysiological indices) of fear generalization in anxiety-related disorder vs. comparison groups. We conducted systematic searches of electronic databases (conducted from January-October 2020) for fear generalization studies involving anxiety-related disorder groups or subclinical analog groups. A total of 300 records were full-text screened and two unpublished datasets were obtained, yielding 16 studies reporting behavioral fear generalization measures. Random-effects meta-analytic models and meta-regressions were applied to the identified data. Fear generalization was significantly heightened in anxiety-related disorder participants (N = 439) relative to comparison participants (N = 428). We did not identify any significant clinical, sample, or methodological moderators. Heightened fear generalization is quantitatively supported as distinguishing anxiety-related disorder groups from comparison groups. Evidence suggests this effect is transdiagnostic, relatively robust to experimental or sample parameters, and that generalization paradigms are a well-supported framework for neurobehavioral investigations of learning and emotion in anxiety-related disorders. We discuss these findings in the context of prior fear conditioning meta-analyses, past neuroimaging investigations of fear generalization in anxiety-related disorders, and future directions and challenges for the field.

Heightened generalized conditioned fear and avoidance in women and underlying psychological processes

Heightened generalization of conditioned fear and avoidance to safe stimuli resembling threat is a key feature of pathological anxiety and might contribute to the increased prevalence of anxiety-related disorders among women. Though animal studies have documented over-generalized fear in female versus male rodents, analogous work in humans is sparse, and no studies to date have examined gender differences in generalized avoidance. We addressed this gap by testing 170 self-identified women (n = 85) and men (n = 85) using a video game-based task assessing generalized Pavlovian fear (perceived threat, fear-potentiated startle) and generalized instrumental avoidance. Instrumental measures of generalization reflected maladaptive avoidance by virtue of being unnecessary to secure safety and incurring a cost of losing the game in which the task is embedded. Women displayed increases in both Pavlovian generalization of perceived threat and maladaptive generalized avoidance. Additionally, decreased motivation to win the game among women mediated the effect of gender on generalized avoidance, and generalized perceived risk and tendencies toward experiential avoidance positively predicted generalized avoidance in women but not men. Overall, findings implicate the undue spread of fear and avoidance to safe stimuli resembling danger among women as a candidate mechanism for differential rates of clinical anxiety across the genders.

Reducing Generalization of Conditioned Fear: Beneficial Impact of Fear Relevance and Feedback in Discrimination Training.

Anxiety patients over-generalize fear, possibly because of an incapacity to discriminate threat and safety signals. Discrimination trainings are promising approaches for reducing such fear over-generalization. Here we investigated the efficacy of a fear-relevant vs. a fear-irrelevant discrimination training on fear generalization and whether the effects are increased with feedback during training. Eighty participants underwent two fear acquisition blocks, during which one face (conditioned stimulus, CS+), but not another face (CS−), was associated with a female scream (unconditioned stimulus, US). During two generalization blocks, both CSs plus four morphs (generalization stimuli, GS1–GS4) were presented. Between these generalization blocks, half of the participants underwent a fear-relevant discrimination training (discrimination between CS+ and the other faces) with or without feedback and the other half a fear-irrelevant discrimination training (discrimination between the width of lines) with or without feedback. US expectancy, arousal, valence ratings, and skin conductance responses (SCR) indicated successful fear acquisition. Importantly, fear-relevant vs. fear-irrelevant discrimination trainings and feedback vs. no feedback reduced generalization as reflected in US expectancy ratings independently from one another. No effects of training condition were found for arousal and valence ratings or SCR. In summary, this is a first indication that fear-relevant discrimination training and feedback can improve the discrimination between threat and safety signals in healthy individuals, at least for learning-related evaluations, but not evaluations of valence or (physiological) arousal.

Generalization of conditioned fear along a dimension of increasing positive valence

The amount of fear evoked by potential threats is oftentimes proportional to the overlap in shared features with known threats. An adaptive learning system should therefore extract relevant features from threat stimuli to successfully detect other novel threats in the environment. But what if the most relevant feature of a threat stimulus is emotionally positive? Here, we used Pavlovian fear conditioning to ask whether people extract positive emotional features of a fear conditioned stimulus (CS) to selectively generalize to other stimuli that contain positive features. In a between subjects design, we first paired a picture of a face expressing either a slight amount of happiness or fear with an electrical shock to the wrist. We then tested fear generalization to modified face stimuli of the same identity expressing more or less happiness or fear. Both groups exhibited biased physiological arousal (a peak shift) to a face stimulus with the most exaggerated emotional expression, regardless of valence. Fear generalization diminished to unreinforced happy faces over the course of testing, whereas arousal was maintained to unreinforced fearful faces throughout testing. Finally, subjects fear conditioned to a slightly happy face were accurate at retrospectively identifying the correct CS, whereas subjects fear conditioned to a fearful face retrospectively misidentified a more fearful face as the threat CS. These findings suggest that positive emotional features extracted from a known threat can guide biased fear generalization, but that generalization is maintained by a dimension of increasing fear which also produces retrospective biases in threat intensity estimation.

Context-dependent generalization of conditioned responses to threat and safety signals

Contextual information can modulate the conditioned response to a threat signal (conditioned stimulus, CS+): fear responses are either potentiated or attenuated depending on whether the context is threatening or safe. In this study, we investigated the influence of context on conditioned fear as well as on generalization of conditioned fear. Thirty-two participants underwent a cue-in-context learning protocol in virtual reality (VR). On Day 1 (acquisition), participants received a mild painful electric shock (unconditioned stimulus, US) in one virtual room (fear context, CTX+) at the offset of one colored light (CS+), but never at the offset of another colored light (CS-). In a second room (safety context, CTX-), the two lights were also presented, but not the US. Successful cue conditioning was indicated by aversive ratings and startle potentiation but not skin conductance responses (SCR) to CS+ versus CS- in CTX+ and not in CTX-. On Day 2 (generalization), participants re-visited both fear and safety contexts plus a generalization context (G-CTX), which was an equal mix of CTX+ and CTX-. The two CSs were shown again in all three contexts. Generalization of conditioned fear was revealed in affective ratings (CS+ was rated more aversive than CS- in G-CTX), but not in physiological measures (equal startle potentiation to CS+ versus CS- in all contexts). In sum, contextual information modulates the responses to a threat signal such that a safety context can inhibit conditioned fear. Interestingly, generalization processes also depend on contextual information.

The role of the medial prefrontal cortex in the generalization of conditioned fear.

Fear generalization, the generalization of fear to innocuous stimuli, is a characteristic component of pathological anxiety. Neural models of fear generalization suggest the involvement of the medial prefrontal cortex (mPFC). However, conflicting empirical findings complicate our understanding of the role of the mPFC in pathological anxiety. To address important unanswered questions in this area, a detailed review and synthesis of results from human and nonhuman animal investigations of conditioned fear generalization was conducted. Empirical articles were identified through March 2017 and selected if they used fear conditioning, measured fear generalization, and included a measure of activity in the mPFC or manipulation of mPFC functioning. In human cued fear conditioning, the ventral mPFC plays an important role in the inhibition of fear generalization, whereas dorsal mPFC is important for the activation of generalized fear. This pattern remains to be further investigated in nonhuman animal models. Nonhuman animal research suggests an interaction between the neural correlates of contextual fear generalization and timing, such that the mPFC appears to increase fear generalization at remote time points and reduce generalization at recent time points following acquisition. The literature suggests a key role for the mPFC in fear generalization, but empirical details vary depending on specific regions within the mPFC, the animal model used, and the timing of the generalization test. Further research is needed to elucidate the role of the mPFC in fear generalization, which could in turn facilitate more effective pharmacological interventions for pathological anxiety. (PsycINFO Database Record

Clinically Anxious Individuals Show Disrupted Feedback between Inferior Frontal Gyrus and Prefrontal-Limbic Control Circuit.

Clinical anxiety is associated with generalization of conditioned fear, in which innocuous stimuli elicit alarm. Using Pavlovian fear conditioning (electric shock), we quantify generalization as the degree to which subjects' neurobiological responses track perceptual similarity gradients to a conditioned stimulus. Previous studies show that the ventromedial prefrontal cortex (vmPFC) inversely and ventral tegmental area directly track the gradient of perceptual similarity to the conditioned stimulus in healthy individuals, whereas clinically anxious individuals fail to discriminate. Here, we extend this work by identifying specific functional roles within the prefrontal-limbic circuit. We analyzed fMRI time-series acquired from 57 human subjects during a fear generalization task using entropic measures of circuit-wide regulation and feedback (power spectrum scale invariance/autocorrelation), in combination with structural (diffusion MRI-probabilistic tractography) and functional (stochastic dynamic causal modeling) measures of prefrontal-limbic connectivity within the circuit. Group comparison and correlations with anxiety severity across 57 subjects revealed dysregulatory dynamic signatures within the inferior frontal gyrus (IFG), which our prior work has linked to impaired feedback within the circuit. Bayesian model selection then identified a fully connected prefrontal-limbic model comprising the IFG, vmPFC, and amygdala. Dysregulatory IFG dynamics were associated with weaker reciprocal excitatory connectivity between the IFG and the vmPFC. The vmPFC exhibited inhibitory influence on the amygdala. Our current results, combined with our previous work across a threat-perception spectrum of 137 subjects and a meta-analysis of 366 fMRI studies, dissociate distinct roles for three prefrontal-limbic regions, wherein the IFG provides evaluation of stimulus meaning, which then informs the vmPFC in inhibiting the amygdala. Affective neuroscience has generally treated prefrontal regions (orbitofrontal cortex, dorsolateral prefrontal cortex, inferior frontal gyrus, ventromedial prefrontal cortex) equivalently as inhibitory components of the prefrontal-limbic system. Yet research across the anxiety spectrum suggests that the inferior frontal gyrus may have a more complex role in emotion regulation, as this region shows abnormal function in disorders of both hyperarousal and hypoarousal. Using entropic measures of circuit-wide regulation and feedback, in combination with measures of structural and functional connectivity, we dissociate distinct roles for three prefrontal-limbic regions, wherein the inferior frontal gyrus provides evaluation of stimulus meaning, which then informs the ventromedial prefrontal cortex in inhibiting the amygdala. This reconfiguration coheres with studies of conceptual disambiguation also implicating the inferior frontal gyrus.

Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder.

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.

Postnatal maturation of GABAergic modulation of sensory inputs onto lateral amygdala principal neurons.

Throughout life, fear learning is indispensable for survival and neural plasticity in the lateral amygdala underlies this learning and storage of fear memories. During development, properties of fear learning continue to change into adulthood, but currently little is known about changes in amygdala circuits that enable these behavioural transitions. In recordings from neurons in lateral amygdala brain slices from infant up to adult mice, we show that spontaneous and evoked excitatory and inhibitory synaptic transmissions mature into adolescence. At this time, increased inhibitory activity and signalling has the ability to restrict the function of excitation by presynaptic modulation, and may thus enable precise stimulus associations to limit fear generalization from adolescence onward. Our results provide a basis for addressing plasticity mechanisms that underlie altered fear behaviour in young animals. Convergent evidence suggests that plasticity in the lateral amygdala (LA) participates in acquisition and storage of fear memory. Sensory inputs from thalamic and cortical areas activate principal neurons and local GABAergic interneurons, which provide feed-forward inhibition that tightly controls LA activity and plasticity via pre- and postsynaptic GABAA and GABAB receptors. GABAergic control is also critical during fear expression, generalization and extinction in adult animals. During rodent development, properties of fear and extinction learning continue to change into early adulthood. Currently, few studies have assessed physiological changes in amygdala circuits that may enable these behavioural transitions. To obtain first insights, we investigated changes in spontaneous and sensory input-evoked inhibition onto LA principal neurons and then focused on GABAB receptor-mediated modulation of excitatory sensory inputs in infant, juvenile, adolescent and young adult mice. We found that spontaneous and sensory-evoked inhibition increased during development. Physiological changes were accompanied by changes in dendritic morphology. While GABAB heteroreceptors were functionally expressed on sensory afferents already early in development, they could only be physiologically recruited by sensory-evoked GABA release to mediate heterosynaptic inhibition from adolescence onward. Furthermore, we found GABAB -mediated tonic inhibition of sensory inputs by ambient GABA that also emerged in adolescence. The observed increase in GABAergic drive may be a substrate for providing modulatory GABA. Our data suggest that GABAB -mediated tonic and evoked presynaptic inhibition can suppress sensory input-driven excitation in the LA to enable precise stimulus associations and limit generalization of conditioned fear from adolescence onward.

Prefrontal NMDA receptors expressed in excitatory neurons control fear discrimination and fear extinction

N-methyl-D-aspartate receptors (NMDARs) are critically involved in various learning mechanisms including modulation of fear memory, brain development and brain disorders. While NMDARs mediate opposite effects on medial prefrontal cortex (mPFC) interneurons and excitatory neurons, NMDAR antagonists trigger profound cortical activation. The objectives of the present study were to determine the involvement of NMDARs expressed specifically in excitatory neurons in mPFC-dependent adaptive behaviors, specifically fear discrimination and fear extinction. To achieve this, we tested mice with locally deleted Grin1 gene encoding the obligatory NR1 subunit of the NMDAR from prefrontal CamKIIα positive neurons for their ability to distinguish frequency modulated (FM) tones in fear discrimination test. We demonstrated that NMDAR-dependent signaling in the mPFC is critical for effective fear discrimination following initial generalization of conditioned fear. While mice with deficient NMDARs in prefrontal excitatory neurons maintain normal responses to a dangerous fear-conditioned stimulus, they exhibit abnormal generalization decrement. These studies provide evidence that NMDAR-dependent neural signaling in the mPFC is a component of a neural mechanism for disambiguating the meaning of fear signals and supports discriminative fear learning by retaining proper gating information, viz. both dangerous and harmless cues. We also found that selective deletion of NMDARs from excitatory neurons in the mPFC leads to a deficit in fear extinction of auditory conditioned stimuli. These studies suggest that prefrontal NMDARs expressed in excitatory neurons are involved in adaptive behavior.

The Impact of Instructions on Generalization of Conditioned Fear in Humans

Generalization of conditioned fear has been implicated in the maintenance and proliferation of fear in anxiety disorders. The role of cognitive processes in generalization of conditioning is an important yet understudied issue. Vervliet et al. (2010) tested generalization of fear to a visual stimulus of a particular color and shape paired with electric shock. Test stimuli shared either the color or shape of the CS+. Prior to conditioning, participants were instructed that either color or shape would be predictive of shock. Generalization was stronger to the stimulus containing the instructed feature, suggesting that instructions impacted generalization of fear. However, the result may also reflect the impact of instructions on attention and learning during the conditioning phase. In the present study, the instructional manipulation was given after the conditioning phase to control for any impact of instructions on learning. A similar result to that reported by Vervliet et al. was observed. On self-reported expectancy of shock, generalization was greater to the test stimulus that included the instructed stimulus feature. The same pattern was observed on skin conductance, although it did not reach statistical significance. The findings indicate that explicitly instructed information affected generalization of conditioned fear independently of any impact on learning, pointing to the role of cognitive processes in human fear generalization. They also support the utility of cognitive therapy approaches, which are employed after fear has already developed, in addressing clinical overgeneralization.

Generalization of Contextual Fear in Humans

Enhanced fear responses to cues, which were not associated with the threat but share perceptual characteristics with the threat signal, indicate generalization of conditioned fear. Here, we investigated for the first time generalization processes in contextual fear conditioning. Thirty-two participants were guided through two virtual offices (acquisition phases). Mildly painful electric shocks (unconditioned stimulus, US) were unpredictably delivered in one office (anxiety context, CTX+), but never in the other office (safety context, CTX-). During the generalization test, participants were guided through CTX+, CTX-, and the generalization context (G-CTX), which contained features of both the CTX+ and the CTX-, but no US was delivered. We found successful contextual fear conditioning (i.e., the CTX+ compared to the CTX- elicited potentiated startle responses and was rated with more negative valence, higher arousal and higher anxiety). Importantly, implicit and explicit responses dissociated in the generalization test. Thus, participants rated the G-CTX as more arousing and anxiogenic than the CTX- indicating anxiety generalization, but they showed enhanced startle responses to the CTX+ only, while the G-CTX and the CTX- did not differ. In summary, healthy participants on an explicit level responded to the generalization context like to the anxiety context, but on an implicit level responded to the generalization context like to the safety context. Possibly, this dissociation suggests distinct and specific generalization processes underlying contextual fear.

Glutamic Acid Decarboxylase 65: A Link Between GABAergic Synaptic Plasticity in the Lateral Amygdala and Conditioned Fear Generalization

An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

Generalized Anxiety Disorder Is Associated With Overgeneralization of Classically Conditioned Fear

Meta-analytic results of fear-conditioning studies in the anxiety disorders implicate generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of anxiety pathology. Due to the absence of conditioning studies assessing generalization in generalized anxiety disorder (GAD), results of this meta-analysis do not reveal whether such generalization abnormalities also apply to GAD. The current study fills this gap by behaviorally and psychophysiologically assessing levels of conditioned fear generalization across adults with and without GAD. Twenty-two patients with a DSM-IV-Text Revision diagnosis of GAD and 26 healthy comparison subjects were recruited and tested. The employed generalization paradigm consisted of quasi-randomly presented rings of gradually increasing size, with extreme sizes serving as conditioned danger cues (CS+) and conditioned safety cues. The rings of intermediary size served as generalization stimuli, creating a continuum of similarity between CS+ and conditioned safety cues across which to assess response slopes, referred to as generalization gradients. Primary outcome variables included slopes for fear-potentiated startle (electromyography) and self-reported risk ratings. Behavioral and psychophysiological findings demonstrated overgeneralization of conditioned fear among patients with GAD. Specifically, generalization gradients were abnormally shallow among GAD patients, reflecting less degradation of the conditioned fear response as the presented stimulus differentiated from the CS+. Overgeneralization of conditioned fear to safe encounters resembling feared situations may contribute importantly to the psychopathology of GAD by proliferating anxiety cues in the individual's environment that are then capable of evoking and maintaining anxiety and worry associated with GAD.

Generalization of Conditioned Fear and Obsessive-Compulsive Traits

Generalization of conditioned fear refers to the transfer of the conditioned fear response to stimuli that resemble the original conditioned stimulus. Overgeneralization of conditioned fear has been associated with panic disorder and generalized anxiety disorder and may be relevant to obsessive-compulsive (OC) symptoms as well. This study represents the first attempt to determine the degree to which individuals with high versus low OC traits over generalize conditioned fear. We hypothesized that the high OC individuals, particularly those characterized by overestimation of threat, would show overgeneralization of conditioned fear compared to controls as measured by behavioral and psychophysiological (fear-potentiated startle) measures. The results of this study show an interaction between the high and low Threat Estimation groups as measured by the Obsessive Beliefs Questionnaire, which suggests that those who have a tendency to overestimate threat show overgeneralization of conditioned fear. This finding suggests that the relation between OC symptoms and overgeneralization of conditioned fear may be specific to the high threat estimation component of OC symptoms.

TOWARD AN ACCOUNT OF CLINICAL ANXIETY PREDICATED ON BASIC, NEURALLY MAPPED MECHANISMS OF PAVLOVIAN FEAR-LEARNING: THE CASE FOR CONDITIONED OVERGENERALIZATION

The past two decades have brought dramatic progress in the neuroscience of anxiety due, in no small part, to animal findings specifying the neurobiology of Pavlovian fear-conditioning. Fortuitously, this neurally mapped process of fear learning is widely expressed in humans, and has been centrally implicated in the etiology of clinical anxiety. Fear-conditioning experiments in anxiety patients thus represent a unique opportunity to bring recent advances in animal neuroscience to bear on working, brain-based models of clinical anxiety. The current presentation details the neural basis and clinical relevance of fear conditioning, and highlights generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of clinical anxiety. Studies testing such generalization across a variety of anxiety disorders (panic, generalized anxiety disorder, and social anxiety disorder) with systematic methods developed in animals will next be presented. Finally, neural accounts of overgeneralization deriving from animal and human data will be described with emphasis given to implications for the neurobiology and treatment of clinical anxiety.