Unconditioned stimulus devaluation decreases the generalization of costly safety behaviors.

Safety behaviors are often maladaptive in clinical anxiety as they typically persist without realistic threat and cause various impairments. In the laboratory, safety behaviors are modelled by responses to a conditioned stimulus (CS) that reduce the occurrence of an expected aversive unconditioned stimulus (US). Preliminary evidence suggests that US devaluation, a procedure that decreases US aversiveness, devalues the threat value of the CS and thus diminishes safety behaviors to the CS. This study (n = 78) aimed to extend this finding and examined whether US-devaluation can reduce the generalization of safety behaviors to various stimuli. After acquiring safety behaviors to CSs of different categories, the US predicted by one CS category was devalued. In test, participants showed a selective reduction in safety behaviors to novel stimuli of the devalued CS category, reflecting a decrease in generalization of safety behaviors. Trait anxiety was associated with persistent generalized safety behaviors to novel stimuli of the devalued category. We discuss how US devaluation may improve treatment outcome but also the challenges of clinical translation.

Reduction of costly safety behaviors after extinction with a generalization stimulus is determined by individual differences in generalization rules.

Exposure-based treatment involves repeated presentation of feared stimuli or situations in the absence of perceived threat (i.e., extinction learning). However, the stimulus or situation of fear acquisition (CS+) is highly unlikely to be replicated and presented during treatment. Thereby, stimuli that resemble the CS+ (generalization stimuli; GSs) are typically presented. Preliminary evidence suggests that depending on how one generalizes fear (i.e., different generalization rules), presenting the same GS in extinction leads to differential effectiveness of extinction learning. The current study aimed to extend this finding to safety behaviors. After differential fear and avoidance conditioning, participants exhibited discrete generalization gradients that were consistent with their reported generalization rules (Similarity vs Linear). The Linear group showed stronger safety behaviors to a selected GS compared to the Similarity group, presumably due to higher threat expectancy. After extinction learning to this GS, the Linear group exhibited stronger reduction in safety behaviors generalization compared to the Similarity group. The results show that identifying distinct generalization rules allows one to predict expectancy violation to the extinction stimulus, in addition to corroborating the idea that strongly violating threat expectancy leads to better extinction learning and its generalization. With regard to clinical implications, identifying one's generalization rule (e.g., threat beliefs) help designing exposure sessions that evoke strong expectancy violation, enhancing the reduction in the generalization of maladaptive safety behaviors.

Fear learning and extinction predicts anxiety in daily life: a study of Pavlovian conditioning and ecological momentary assessment.

BACKGROUND: The association between anxious mood and aberrant fear learning mechanisms has not been fully elucidated. Studying how fear conditioning and extinction constructs relate to anxiety symptoms and reactivity to stressful and benign moments in everyday life provides a powerful addition to experimental paradigms. METHOD: Fifty-one young adults completed laboratory-based differential conditioning and extinction tasks with (CS + ) and without (CS-) an aversive unconditional stimulus (US). Electrodermal skin conductance responses were measured during each phase, followed by ecological momentary assessment (EMA) tapping anxiety and stressors six times daily for seven days (2, 142 moments). RESULTS: Conditioned electrodermal reactivity to the CS + and overgeneralisation to the CS- were associated with greater change in anxiety (measured via EMA), across non-stressful situations, remaining the same across stressful situations. Likewise, during extinction when the CS + is now safe, more electrodermal reactivity to the CS + was associated with more anxiety change across non-stressful situations and remained the same across stressful situations. Also, during extinction when threat is absent, more electrodermal reactivity at the late stage of the CS- was associated with less momentary anxiety change in response to stressful situations; more electrodermal activity at the late stage of the CS + was associated with more anxiety change across non-stressful situations and remained the same across stressful situations. CONCLUSIONS: Sampling 'in vivo' emotion and stress experiences, study findings revealed links between conditioned electrodermal reactivity and overgeneralisation to safe stimuli and heightened anxious reactivity during non-stressful (i.e. safe) moments in daily life, coupled with less change in response to actual stressors.

Neural adaptation of cingulate and insular activity during delayed fear extinction: A replicable pattern across assessment sites and repeated measurements.

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24 h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.

Assessment of the abuse potential of methamnetamine in rodents: a behavioral pharmacology study.

RATIONALE: Methamnetamine (MNA; PAL-1046) is a new psychoactive substance that acts as a full biogenic amine transporter (BAT) substrate. BAT substrates promote neurotransmitter release from the nerve terminal and can be abused as stimulants. However, scientific information on the abuse potential of methamnetamine is lacking. OBJECTIVE: We evaluated the abuse liability of methamnetamine. METHODS: The effective dose range of methamnetamine was determined using a climbing behavior test. The rewarding effect and reinforcing effect of the test compound were evaluated in mice by conditioned place preference (CPP) testing and self-administration (SA) testing at the selected doses. Dopamine level changes were analyzed using synaptosomes and in vivo microdialysis to investigate the effects of methamnetamine on the central nervous system. Drug discrimination experiments were used to examine the potential similarity of the interoceptive effects of methamnetamine and cocaine. RESULTS: A significant response was observed in the climbing behavior test with 10 and 40 mg/kg intraperitoneally administered methamnetamine. In the CPP test, mice intraperitoneally administered methamnetamine (10 and 20 mg/kg) showed a significant preference for the drug-paired compartment. In the SA test, mice that intravenously received 1 mg/kg/infusion showed significant active-lever responses. Dopamine was significantly increased in synaptosomes and in in vivo microdialysis tests. Furthermore, methamnetamine showed cross-generalization with cocaine in a dose-dependent manner. CONCLUSIONS: Methamnetamine exhibits interceptive stimulus properties similar to those of cocaine and induces rewarding and reinforcing effects, suggesting its dependence liability potential.

Costly avoidance triggered by categorical fear generalization.

Fear generalization refers to the spread of acquired fear to novel stimuli that resemble the original fear-related stimulus. Preliminary evidence suggests that excessive fear generalization is a pathogenic feature of anxiety disorders, however, it remains unclear how fear generalization affects pathological avoidance. The current study thus aimed to examine the link between categorical fear generalization and costly avoidance. By combining a fear acquisition training phase and an avoidance test, the current findings showed that acquired fear spreads to novel stimuli that belonged to the same category of the original fear-related stimuli, but not to those that belonged to the fear-irrelevant categories. Importantly, participants avoided these fear-related novel stimuli despite costs. The current findings indicate that categorical fear generalization triggers costly avoidance. In terms of clinical implication, a decrease in costly avoidance aligned with a decrease in US expectancies. This emphasizes that behavioral approach may initiate extinction learning.

Negative life experiences contribute to racial differences in the neural response to threat.

Threat-related emotional function is supported by a neural circuit that includes the prefrontal cortex (PFC), hippocampus, and amygdala. The function of this neural circuit is altered by negative life experiences, which can potentially affect threat-related emotional processes. Notably, Black-American individuals disproportionately endure negative life experiences compared to White-American individuals. However, the relationships among negative life experiences, race, and the neural substrates that support threat-related emotional function remains unclear. Therefore, the current study investigated whether the brain function that supports threat-related emotional processes varies with racial differences in negative life experiences. In the present study, adolescent violence exposure, family income, and neighborhood disadvantage were measured prospectively (i.e., at 11-19 years of age) for Black-American and White-American volunteers. Participants then, as young adults (i.e., 18-23 years of age), completed a Pavlovian fear conditioning task during functional magnetic resonance imaging (fMRI). Cued and non-cued threats were presented during the conditioning task and behavioral (threat expectancy) and psychophysiological responses (skin conductance response; SCR) were recorded simultaneously with fMRI. Racial differences were observed in neural (fMRI activity), behavioral (threat expectancy), and psychophysiological (SCR) responses to threat. These threat-elicited responses also varied with negative life experiences (violence exposure, family income, and neighborhood disadvantage). Notably, racial differences in brain activity to threat were smaller after accounting for negative life experiences. The present findings suggest that racial differences in the neural and behavioral response to threat are due, in part, to exposure to negative life experiences and may provide new insight into the mechanisms underlying racial disparities in mental health.

Cues play a critical role in estrous cycle-dependent enhancement of cocaine reinforcement.

While preclinical work has aimed to outline the neural mechanisms of drug addiction, it has overwhelmingly focused on male subjects. There has been a push in recent years to incorporate females into existing addiction models; however, males and females often have different behavioral strategies, making it important to not only include females, but to develop models that assess the factors that comprise female drug addiction. Traditional self-administration models often include light or tone cues that serve as discriminative stimuli and/or consequent stimuli, making it nearly impossible to disentangle the effects of cue learning, the cues themselves, and acute effects of psychostimulant drugs. To disentangle the interaction between drug-associated cues and the consummatory and appetitive responding driven by cocaine, we have developed a new behavioral procedure that combines Pavlovian-instrumental transfer with behavioral economic analysis. This task can be completed within a single session, allowing for studies looking at estrous cycle stage-dependent effects in intact cycling females, something that has been difficult in the past. In this study, we found no differences in self-administration across the estrous cycle in the absence of cues; however, when cues were introduced, the cues that acquired value during estrus-but not during diestrus or in males-increased motivation. Cues paired during estrus also increased c-fos expression to a greater extent in striatal regions, an effect that may underlie the observed increases in seeking induced by these cues, even weeks later. Together, these data suggest that fundamental differences in the motivational properties of psychostimulant drugs between males and females are complex and are driven primarily by the interaction between drug-associated stimuli and drug effects.

Living in fear: Low-cost avoidance maintains low-level threat.

BACKGROUND AND OBJECTIVES: Excessive avoidance of potential threat is a hallmark of anxiety and is thought to maintain fear by preserving the perceived high-threat value of avoided situations. Previous research has shown that the availability of avoidance maintains low-level threat. Here, we investigated whether an opportunity to engage in avoidance in the presence of a low-threat value safety cue would maintain its perceived threat value when avoidance was unavailable. METHODS: In a threat conditioning procedure, one conditional danger stimulus (CS+; A+) was followed by an aversive unconditioned stimulus (US; electric shock), and two safety stimuli (CS-; B- and C-) were never followed by the US. Next, clicking a button present during A+ avoided the scheduled US. Avoidance was then made available during C- for participants in the Experimental group but not in the Control group. In the test, all stimuli were presented without the opportunity to avoid. Threat expectancy, eyeblink startle electromyography (EMG), and skin conductance responses (SCRs) were measured. RESULTS: Findings showed an increase in threat expectancy for only C- in the Experimental group during the test phase following avoidance learning to similar levels as during threat conditioning. Compared to the Control group, threat expectancy for both B- and C- remained higher in Experimental group. SCR and startle EMG data did not corroborate these findings. LIMITATIONS: Further research is needed to test the commonly held clinical assumption that avoidance can increase threat value. CONCLUSIONS: Low-cost avoidance maintains low-threat value of safety cues.

Mesolimbic Dopamine and the Regulation of Motivated Behavior.

It has been known for some time that nucleus accumbens dopamine (DA) is involved in aspects of motivation , but theoretical approaches to understanding the functions of DA have continued to evolve based upon emerging data and novel concepts. Although it has become traditional to label DA neurons as "reward" neurons, the actual findings are more complicated than that, because they indicate that DA neurons can respond to a variety of motivationally significant stimuli. Moreover, it is important to distinguish between aspects of motivation that are differentially affected by dopaminergic manipulations. Studies that involve nucleus accumbens DA antagonism or depletion indicate that accumbens DA does not mediate primary food motivation or appetite. Nevertheless, DA is involved in appetitive and aversive motivational processes including behavioral activation , exertion of effort, sustained task engagement, and Pavlovian-to-instrumental transfer. Interference with accumbens DA transmission affects instrumental behavior in a manner that interacts with the response requirements of the task and also shifts effort-related choice behavior, biasing animals toward low-effort alternatives. Dysfunctions of mesolimbic DA may contribute to motivational symptoms seen in various psychopathologies, including depression , schizophrenia, parkinsonism, and other disorders.

Fear-potentiated startle processing in humans: Parallel fMRI and orbicularis EMG assessment during cue conditioning and extinction.

Studying neural networks and behavioral indices such as potentiated startle responses during fear conditioning has a long tradition in both animal and human research. However, most of the studies in humans do not link startle potentiation and neural activity during fear acquisition and extinction. Therefore, we examined startle blink responses measured with electromyography (EMG) and brain activity measured with functional MRI simultaneously during differential conditioning. Furthermore, we combined these behavioral fear indices with brain network activity by analyzing the brain activity evoked by the startle probe stimulus presented during conditioned visual threat and safety cues as well as in the absence of visual stimulation. In line with previous research, we found a fear-induced potentiation of the startle blink responses when elicited during a conditioned threat stimulus and a rapid decline of amygdala activity after an initial differentiation of threat and safety cues in early acquisition trials. Increased activation during processing of threat cues was also found in the anterior insula, the anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). More importantly, our results depict an increase of brain activity to probes presented during threatening in comparison to safety cues indicating an involvement of the anterior insula, the ACC, the thalamus, and the PAG in fear-potentiated startle processing during early extinction trials. Our study underlines that parallel assessment of fear-potentiated startle in fMRI paradigms can provide a helpful method to investigate common and distinct processing pathways in humans and animals and, thus, contributes to translational research.

Fatal attraction: ventral striatum predicts costly choice errors in humans.

Animals approach rewards and cues associated with reward, even when this behavior is irrelevant or detrimental to the attainment of these rewards. Motivated by these findings we study the biology of financially-costly approach behavior in humans. Our subjects passively learned to predict the occurrence of erotic rewards. We show that neuronal responses in ventral striatum during this Pavlovian learning task stably predict an individual's general tendency towards financially-costly approach behavior in an active choice task several months later. Our data suggest that approach behavior may prevent some individuals from acting in their own interests.

Multimodal assessment of long-term memory recall and reinstatement in a combined cue and context fear conditioning and extinction paradigm in humans.

Learning to predict danger via associative learning processes is critical for adaptive behaviour. After successful extinction, persisting fear memories often emerge as returning fear. Investigation of return of fear phenomena, e.g. reinstatement, have only recently began and to date, many critical questions with respect to reinstatement in human populations remain unresolved. Few studies have separated experimental phases in time even though increasing evidence shows that allowing for passage of time (and consolidation) between experimental phases has a major impact on the results. In addition, studies have relied on a single psychophysiological dimension only (SCRs/SCL or FPS) which hampers comparability between different studies that showed both differential or generalized return of fear following a reinstatement manipulation. In 93 participants, we used a multimodal approach (fear-potentiated startle, skin conductance responses, fear ratings to asses fear conditioning (day 1), extinction (day 2) as well as delayed memory recall and reinstatement (day 8) in a paradigm that probed contextual and cued fear intra-individually. Our findings show persistence of conditioning and extinction memory over time and demonstrate that reinstated fear responses were qualitatively different between dependent variables (subjective fear ratings, FPS, SCRs) as well as between cued and contextual CSs. While only the arousal-related measurement (SCRs) showed increasing reactions following reinstatement to the cued CSs, no evidence of reinstatement was observed for the subjective ratings and fear-related measurement (FPS). In contrast, for contextual CSs, reinstatement was evident as differential and generalized reinstatement in fear ratings as well as generally elevated physiological fear (FPS) and arousal (SCRs) related measurements to all contextual CSs (generalized non-differential reinstatement). Returning fear after reinstatement likely depends on a variety of variables (experimental design, dependent measurements) and more systematic investigations with respect to critical determinants of reinstatement in humans are required.

A further assessment of the Hall-Rodriguez theory of latent inhibition.

The Hall-Rodriguez (G. Hall & G. Rodriguez, 2010, Associative and nonassociative processes in latent inhibition: An elaboration of the Pearce-Hall model, in R. E. Lubow & I. Weiner, Eds., Latent inhibition: Data, theories, and applications to schizophrenia, pp. 114-136, Cambridge, England: Cambridge University Press) theory of latent inhibition predicts that it will be deepened when a preexposed target stimulus is given additional preexposures in compound with (a) a novel stimulus or (b) another preexposed stimulus, and (c) that deepening will be greater when the compound contains a novel rather than another preexposed stimulus. A series of experiments studied these predictions using a fear conditioning procedure with rats. In each experiment, rats were preexposed to 3 stimuli, 1 (A) taken from 1 modality (visual or auditory) and the remaining 2 (X and Y) taken from another modality (auditory or visual). Then A was compounded with X, and Y was compounded with a novel stimulus (B) taken from the same modality as A. A previous series of experiments (H. T. Leung, A. S. Killcross, & R. F. Westbrook, 2011, Additional exposures to a compound of two preexposed stimuli deepen latent inhibition, Journal of Experimental Psychology: Animal Behavior Processes, Vol. 37, pp. 394-406) compared A with Y, finding that A was more latently inhibited than Y, the opposite of what was predicted. The present experiments confirmed that A was more latently inhibited than Y, showed that this was due to A entering the compound more latently inhibited than Y, and finally, that a comparison of X and Y confirmed the 3 predictions made by the theory.

Neural prediction errors reveal a risk-sensitive reinforcement-learning process in the human brain.

Humans and animals are exquisitely, though idiosyncratically, sensitive to risk or variance in the outcomes of their actions. Economic, psychological, and neural aspects of this are well studied when information about risk is provided explicitly. However, we must normally learn about outcomes from experience, through trial and error. Traditional models of such reinforcement learning focus on learning about the mean reward value of cues and ignore higher order moments such as variance. We used fMRI to test whether the neural correlates of human reinforcement learning are sensitive to experienced risk. Our analysis focused on anatomically delineated regions of a priori interest in the nucleus accumbens, where blood oxygenation level-dependent (BOLD) signals have been suggested as correlating with quantities derived from reinforcement learning. We first provide unbiased evidence that the raw BOLD signal in these regions corresponds closely to a reward prediction error. We then derive from this signal the learned values of cues that predict rewards of equal mean but different variance and show that these values are indeed modulated by experienced risk. Moreover, a close neurometric-psychometric coupling exists between the fluctuations of the experience-based evaluations of risky options that we measured neurally and the fluctuations in behavioral risk aversion. This suggests that risk sensitivity is integral to human learning, illuminating economic models of choice, neuroscientific models of affective learning, and the workings of the underlying neural mechanisms.

Average group behavior does not represent individual behavior in classical conditioning of the honeybee.

Conditioned behavior as observed during classical conditioning in a group of identically treated animals provides insights into the physiological process of learning and memory formation. However, several studies in vertebrates found a remarkable difference between the group-average behavioral performance and the behavioral characteristics of individual animals. Here, we analyzed a large number of data (1640 animals) on olfactory conditioning in the honeybee (Apis mellifera). The data acquired during absolute and differential classical conditioning differed with respect to the number of conditioning trials, the conditioned odors, the intertrial intervals, and the time of retention tests. We further investigated data in which animals were tested for spontaneous recovery from extinction. In all data sets we found that the gradually increasing group-average learning curve did not adequately represent the behavior of individual animals. Individual behavior was characterized by a rapid and stable acquisition of the conditioned response (CR), as well as by a rapid and stable cessation of the CR following unrewarded stimuli. In addition, we present and evaluate different model hypotheses on how honeybees form associations during classical conditioning by implementing a gradual learning process on the one hand and an all-or-none learning process on the other hand. In summary, our findings advise that individual behavior should be recognized as a meaningful predictor for the internal state of a honeybee--irrespective of the group-average behavioral performance.

Reward skewness coding in the insula independent of probability and loss.

Rewards in the natural environment are rarely predicted with complete certainty. Uncertainty relating to future rewards has typically been defined as the variance of the potential outcomes. However, the asymmetry of predicted reward distributions, known as skewness, constitutes a distinct but neuroscientifically underexplored risk term that may also have an impact on preference. By changing only reward magnitudes, we study skewness processing in equiprobable ternary lotteries involving only gains and constant probabilities, thus excluding probability distortion or loss aversion as mechanisms for skewness preference formation. We show that individual preferences are sensitive to not only the mean and variance but also to the skewness of predicted reward distributions. Using neuroimaging, we show that the insula, a structure previously implicated in the processing of reward-related uncertainty, responds to the skewness of predicted reward distributions. Some insula responses increased in a monotonic fashion with skewness (irrespective of individual skewness preferences), whereas others were similarly elevated to both negative and positive as opposed to no reward skew. These data support the notion that the asymmetry of reward distributions is processed in the brain and, taken together with replicated findings of mean coding in the striatum and variance coding in the cingulate, suggest that the brain codes distinct aspects of reward distributions in a distributed fashion.

Conditioning with masked stimuli affects the timecourse of skin conductance responses.

In Pavlovian fear conditioning, an aversive unconditional stimulus (UCS) is repeatedly paired with a neutral conditional stimulus (CS). As a consequence, the subject begins to show conditional responses (CRs) to the CS that indicate expectation and fear. There are currently two general models competing to explain the role of subjective awareness in fear conditioning. Proponents of the single-process model assert that a single propositional learning process mediates CR expression and UCS expectancy. Proponents of a dual-process model assert that these behavioral responses are expressions of two independent learning processes. We used backward masking to block perception of our visual CSs and measured the effect of this training on subsequent unmasked performance. In two separate experiments we show a dissociation between CR expression and UCS expectancy following differential delay conditioning with masked CSs. In Experiment I, we show that masked training facilitates CR expression when the same CSs are presented during a subsequent unmasked reacquisition task. In Experiment II we show that masked training retards learning when the CS+ is presented as part of a compound CS during a subsequent unmasked blocking task. Our results suggest that multiple memory systems operate in a parallel, independent manner to encode emotional memories.

Learning processes affecting human decision making: An assessment of reinforcer-selective Pavlovian-to-instrumental transfer following reinforcer devaluation.

In reinforcer-selective transfer, Pavlovian stimuli that are predictive of specific outcomes bias performance toward responses associated with those outcomes. Although this phenomenon has been extensively examined in rodents, recent assessments have extended to humans. Using a stock market paradigm adults were trained to associate particular symbols and responses with particular currencies. During the first test, individuals showed a preference for responding on actions associated with the same outcome as that predicted by the presented stimulus (i.e., a reinforcer-selective transfer effect). In the second test of the experiment, one of the currencies was devalued. We found it notable that this served to reduce responses to those stimuli associated with the devalued currency. This finding is in contrast to that typically observed in rodent studies, and suggests that participants in this task represented the sensory features that differentiate the reinforcers and their value during reinforcer-selective transfer. These results are discussed in terms of implications for understanding associative learning processes in humans and the ability of reward-paired cues to direct adaptive and maladaptive behavior.

Conditioned associations and economic decision biases.

Humans show substantial deviation from rationality during economic decision making under uncertainty. A computational perspective suggests these deviations arise out of an interaction between distinct valuation systems in the brain. Here, we provide behavioural data showing that the incidental presentation of aversive and appetitive conditioned stimuli can alter subjects' preferences in an economic task, involving a choice between a safe or gamble option. These behavioural effects informed a model-based analysis of a functional magnetic resonance imaging (fMRI) experiment, involving an identical paradigm, where we demonstrate that this conditioned behavioral bias engages the amygdala, a brain structure associated with acquisition and expression of conditioned associations. Our findings suggest that a well known bias in human economic choice can arise from an influence of conditioned associations on goal-directed decision making, consistent with an architecture of choice that invokes distinct decision-making systems.