Contingency awareness shapes neural responses in fear conditioning

The ability to detect and learn contingencies between fearful stimuli and their predictive cues is an important capacity to cope with the environment. Contingency awareness refers to the ability to verbalize the relationships between conditioned and unconditioned stimuli. Although there is a heated debate about the influence of contingency awareness on conditioned fear responses, neural correlates behind the formation process of contingency awareness have gained only little attention in human fear conditioning. Recent animal studies indicate that the ventral striatum (VS) could be involved in this process, but in human studies the VS is mostly associated with positive emotions. To examine this question, we reanalyzed four recently published classical fear conditioning studies (n = 117) with respect to the VS at three distinct levels of contingency awareness: subjects, who did not learn the contingencies (unaware), subjects, who learned the contingencies during the experiment (learned aware) and subjects, who were informed about the contingencies in advance (instructed aware). The results showed significantly increased activations in the left and right VS in learned aware compared to unaware subjects. Interestingly, this activation pattern was only found in learned but not in instructed aware subjects. We assume that the VS is not involved when contingency awareness does not develop during conditioning or when contingency awareness is unambiguously induced already prior to conditioning. VS involvement seems to be important for the transition from a contingency unaware to a contingency aware state. Implications for fear conditioning models as well as for the contingency awareness debate are discussed.

Serotonin, Stress, and Conditioning

SummaryInvestigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety.

Treatment of addiction and anxiety using extinction approaches: Neural mechanisms and their treatment implications

IntroductionThe recognition of the conditioned-unconditioned stimulus (CS-US) association in classical conditioning is referred to as contingency awareness. The neural underpinnings of contingency awareness in human fear conditioning are poorly understood.ObjectivesWe aimed to explore the EEG correlates of contingency awareness.MethodsHere, we recorded electroencephalography (EEG) from a sample of 20 participants in a semantic conditioning experiment. In the acquisition phase the participants were presented with sequences of words from two semantic categories paired with tactile stimulation followed by presentation of a neutral sound (US-) ((e.g., animals -> left hand vibration -> US-, clothes -> right hand vibration -> US-). In the test phase the association violated in 50% of trials which followed by a presentation of a loud noise (US+). The participants were only instructed to listen carefully. On the basis of self-reported contingency awareness, twenty participants were divided in aware (N=12) and unaware (N=8) group.ResultsThe aware group expressed a non-lateralized effect of alpha-beta (12-23 Hz) suppression along with a more negative CNV at central channels preceding presentation of the vibration (main effect of Group). Also, CNV was more negative in expectation of US+ comparing with expectation of US- in the aware group but not in the unaware group.ConclusionsThe results indicate that contingency awareness is accompanied by neural patterns reflecting expectation as can be seen in the suppression of somatosensory alpha-beta activity before expected presentation of the vibration as well as in CNV in expectation of an aversive event.

Investigating the impact of sex and cortisol on implicit fear conditioning with fMRI

Dissociation of neural responses and skin conductance reactions during fear conditioning with and without awareness of stimulus contingencies

Fear conditioning is a basic learning process which involves the association of a formerly neutral conditioned stimulus (CS) with a biologically relevant aversive unconditioned stimulus (US). Previous studies conducted in brain-lesioned patients have shown that while the acquisition of autonomic fear responses requires an intact amygdala, a spared hippocampus is necessary for the development of the CS-US contingency awareness. Although these data have been supported by studies using functional neuroimaging techniques in healthy people, attempts to extend these findings to the morphological aspects of amygdala and hippocampus are missing. Here we tested the hypothesis that amygdalar and hippocampal volumes play dissociable roles in determining autonomic responses and contingency awareness during fear conditioning. Fifty-two healthy individuals (mean age 21.83) underwent high-resolution magnetic resonance imaging. We used a differential delay fear conditioning paradigm while assessing skin conductance responses (SCRs), subjective ratings of CS-US contingency, as well as emotional valence and perceived arousal. Left amygdalar volume significantly predicted the magnitude of differential SCRs during fear acquisition, but had no impact on contingency learning. Conversely, bilateral hippocampal volumes were significantly related to contingency ratings, but not to SCRs. Moreover, left amygdalar volume predicted SCRs to the reinforced CS alone, but not those elicited by the US. Our findings bridge the gap between previous lesion and functional imaging studies, by showing that amygdalar and hippocampal volumes differentially modulate the acquisition of conditioned fear. Further, our results reveal that the morphology of these limbic structures moderate learning and memory already in healthy persons.

Understanding what an animal learns when exposed to novelty is of great interest to behavioral neuroscientists, but it can be challenging to understand what information is acquired in a particular learning session. The behavior of an animal has to be quantified using either visual or mechanical measures of a particular response. One way of elucidating mechanisms involved in discrete learning sessions is to study associative learning processes. Simplistically, associative learning is an adaptive process that allows an organism to learn to anticipate events.One form of associative learning that has been used in multiple species, including humans, is eye-blink conditioning. The most common species used, the rabbit, has yielded interesting results, especially in identifying and elucidating the involvement of the cerebral cortex. Similar procedures have been used in cats, rats, and humans. Another form of associative learning that has gained popularity with behavioral pharmacologists is fear conditioning. While the eye-blink procedure has overlap with context/cue fear conditioning and in many cases yields similar results, there are some basic differences between fear conditioning and eye-blink conditioning. One main difference is that eye-blink conditioning takes many more training trials to establish. Fear conditioning has gained popularity, in large part as a result of the need to characterize mutant mice and the effects of genetic alterations; therefore, this chapter primarily focuses on fear conditioning.Fear conditioning to either a cue or a context represents a form of associative learning that has been well used in many species [1]. The majority of the experiments reported in the literature involve the mouse; however, there is also a generous proportion of the literature devoted to the rat. There are also several reports in higher species that are not covered in this chapter. In general any of the procedures described in this chapter can be used for either the rat or the mouse.The dependent measure used in contextual and cued (delay or trace) fear conditioning is a freezing response that takes place following pairing of an unconditioned stimulus (US), such as foot shock or air puff, with a conditioned stimulus (CS), a particular context and/or such a cue. In the case of rats and mice, this US is generally a foot shock. Obviously, if in a conditioning context one administers a foot shock that is paired with a tone, there will be learning not only to the tone, but also to the context. Two types of conditioning that are typically employed are delay or trace conditioning. Delay conditioning refers to a situation in which the US is administered to co-terminate with or occur immediately after the CS. Trace conditioning differs from delay conditioning in that the US follows an empty (“trace”) interval that separates the cessation of the CS from the onset of the US. Trace conditioning adds additional complexity to delay conditioning, as the time interval between the CS and US requires the formation of a temporal relationship between the two stimuli.In this chapter we discuss the various challenges inherent in this type of procedure in order to enable the experimenter to set the conditions to best answer the questions being posed. One of the biggest advantages of cued and contextual fear conditioning in the rodent is that they are forms of passive learning that can be used in many strains of mice and rats, even when more pronounced motor deficits are problematic in other learning assays. As a consequence of these procedural advantages, contextual fear conditioning is gaining popularity, especially in the phenotyping of transgenic mice.

Despite a strong focus on the role of the amygdala in fear conditioning, recent works point to a more distributed network supporting fear conditioning. We aimed to elucidate interactions between subcortical and cortical regions in fear conditioning in humans. To do this, we used two fearful faces as conditioned stimuli (CS) and an electrical stimulation at the left hand, paired with one of the CS, as unconditioned stimulus (US). The luminance of the CS was rhythmically modulated leading to "entrainment" of brain oscillations at a predefined modulation frequency. Steady-state responses (SSR) were recorded by MEG. In addition to occipital regions, spectral analysis of SSR revealed increased power during fear conditioning particularly for thalamus and cerebellum contralateral to the upcoming US. Using thalamus and amygdala as seed-regions, directed functional connectivity was calculated to capture the modulation of interactions that underlie fear conditioning. Importantly, this analysis showed that the thalamus drives the fusiform area during fear conditioning, while amygdala captures the more general effect of fearful faces perception. This study confirms ideas from the animal literature, and demonstrates for the first time the central role of the thalamus in fear conditioning in humans.

In Pavlovian fear conditioning, contingency awareness provides an indicator of explicit fear learning. A less studied aspect of fear-based psychopathologies and their treatment, awareness of learned fear is a common cause of distress in persons with such conditions and is a focus of their treatment. The present work is a substudy of a broader fear-conditioning fMRI study. Following fear conditioning, we identified a subset of individuals who did not exhibit explicit awareness of the CS-US contingency. This prompted an exploratory analysis of differences in "aware" versus "unaware" individuals after fear conditioning. Self-reported expectancies of the CS-US contingency obtained immediately following fear conditioning were used to differentiate the two groups. Results corrected for multiple comparisons indicated significantly greater BOLD signal in the bilateral dlPFC, right vmPFC, bilateral vlPFC, left insula, left hippocampus, and bilateral amygdala for the CS+>CS- contrast in the aware group compared with the unaware group (all p values ≤ 0.004). PPI analysis with a left hippocampal seed indicated stronger coupling with the dlPFC and vmPFC in the aware group compared with the unaware group (all p values ≤ 0.002). Our findings add to our current knowledge of the networks involved in explicit learning and awareness of conditioned fear, with important clinical implications.

In an fMRI study, effects of contingency awareness on conditioned responses were assessed in three groups comprising 118 subjects. A differential fear-conditioning paradigm with visual conditioned stimuli, an electrical unconditioned stimulus and two distractors was applied. The instructed aware group was informed about the contingencies, whereas the distractors prevented contingency detection in the unaware group. The third group (learned aware) was not informed about the contingencies, but learned them despite the distractors. Main effects of contingency awareness on conditioned responses emerged in several brain structures. Post hoc tests revealed differential dorsal anterior cingulate, insula and ventral striatum responses in aware conditioning only, whereas the amygdala was activated independent of contingency awareness. Differential responses of the hippocampus were specifically observed in learned aware subjects, indicating a role in the development of contingency awareness. The orbitofrontal cortex showed varying response patterns: lateral structures showed higher responses in instructed aware than unaware subjects, the opposite was true for medial parts. Conditioned subjective and electrodermal responses emerged only in the two aware groups. These results confirm the independence of conditioned amygdala responses from contingency awareness and indicate specific neural circuits for different aspects of fear acquisition in unaware, learned aware and instructed aware subjects.

The human cerebellum contributes to motor, emotional and cognitive associative learning. A review

Unconditioned stimulus pathways to the amygdala: effects of posterior thalamic and cortical lesions on fear conditioning

The amygdala has long been recognized as crucial for the processing of emotional information, especially fear and negative affect. In this article (Boll et al., 2012), the authors approach amygdala function in human fear conditioning with considerable subtlety. Using high-resolution functional magnetic resonance imaging, they track the updating of processing of both cues and outcomes as participants’ expectancies are first confirmed and then violated. Going beyond other recent investigations (Li et al., 2011), the authors identify subregion-specific amygdala blood oxygen level-dependent responses that separately reflect outcome prediction and prediction error signals. Pavlovian fear conditioning, in which initially meaningless conditioned stimuli (CSs) paired with noxious unconditioned stimuli (USs) acquire the ability to elicit fear, has served as a primary model for studying the neurobiological basis of learning. Much of the research generated by that model has been based on variants of the dictum of Hebb (1949), often paraphrased as ‘systems of cells that fire together, wire together’. The amygdala quickly emerged as a site at which CS and US information converged, and hence could be ‘wired together’ when CSs and USs occurred contiguously in time. However, CS–US contiguity alone is insufficient for associative learning to occur. For example, if a US is already well predicted on the basis of one CS, pairings of a compound of that CS and a new CS with the US often result in little evidence for learning about the new CS, a phenomenon known as ‘blocking’. To deal with many such observations, most learning theories of the past 40 years incorporate the idea that new learning depends critically on prediction error, the difference between expected and received outcomes. Within these models, the importance of CS–US contiguity in the establishment of associations is reaffirmed, but processing of either the CS, the US, or both, is modulated by prediction error, such that unexpected USs or the CSs that precede them (or both) are processed better than expected USs or their accompanying CSs. Considerable evidence from reward conditioning procedures supports the view that the processing of both CSs and USs is indeed modulated by prediction error, and has indicated a number of brain substrates for this modulation, including midbrain dopamine neurons and the amygdala (Holland & Maddux, 2010). In this study, participants were exposed to a discrimination reversal procedure, in which initially one CS was paired with shock and another CS was not, and later the roles of the two stimuli were reversed. Although a ‘US processing’ model, in which prediction error modulates US effectiveness, fit participants’ ratings of shock expectancy better than a random model, a ‘hybrid’ model that included effects of prediction error on both CS and US processing fared best. The authors examined the amygdala and midbrain blood oxygen level-dependent correlates of CS-induced predictions of shock and its absence, and of the prediction errors induced by the surprising omission or presentation of the shock, when the discrimination was reversed, fitted to the hybrid model. Correlates of unsigned prediction error when the US was unexpectedly presented or omitted were observed in both centromedial amygdala and substantia nigra/ventral tegmental areas, whereas the basolateral amygdala blood oxygen level-dependent response during the CSs was negatively correlated with subsequent prediction error, and hence was related to prediction accuracy. The work nicely demonstrates convergence of human and animal research concerning fundamental issues of learning in the questions posed (what are the consequences of the confirmation and violation of learned expectancies for information processing), the approaches taken (quantitative modeling based on well-documented theories of learning), and the behavioral and neural processing results obtained, despite differences in species, behavioral measures, and measures of brain activity. The use of common approaches and theoretical perspectives across human and animal studies, each with their own strengths and shortcomings, may provide a unified approach to understanding relations between cognitive and affective processing.