Fear memory uncovered: Prediction error as the key to memory plasticity

Anxiety disorders rank among the most prevalent and chronic forms of psychopathology. While commonly used therapeutic techniques such as exposure therapy are effective in reducing fear, many patients suffer from relapse of fear. This can be explained by the observation that during therapy a new memory is formed that transiently suppresses the original fear memory. According to the traditional view on memory, once an emotional memory has been stored in the brain through the process of consolidation, the memory remains as a permanent trace. Fear reduction was hence considered to be established only through inhibition - but not elimination - of the fear memory. However, exciting insights from neuroscience have shown that by reactivating a consolidated fear memory, it can return to a plastic state. From this plastic state the memory has to reconsolidate in order to endure. The finding that fear memory is more malleable than previously thought is very promising for clinical practice. Nevertheless, the conditions under which reconsolidation does and does not take place remain to be elucidated. In a series of human fear conditioning experiments we investigated the conditions under which a reactivated memory remains stable or is open to modification. With the demonstration that new learning is a prerequisite for reconsolidation, the current thesis shows that memory reconsolidation allows for memory updating. These findings are of relevance for the mechanisms underlying learning and memory by demonstrating the unique role reconsolidation holds in memory plasticity. Clinical practice will hopefully benefit from these insights in the development of new reconsolidation-based therapies for those who suffer from anxiety disorders and PTSD

Personality and Fear Conditioning: Effects of Neuroticism

Fear conditioning is an associative learning paradigm that can be used to examine the acquisition and extinction of learned fear in various populations. Unusual patterns in fear conditioning are known to be associated with different types of psychopathology, and anxiety in particular has been studied extensively in relation to fear conditioning. However, far less is known about fear conditioning in nonclinical samples, particularly with regards to personality. The aim of the current study is to examine the acquisition and extinction of conditioned fear as it relates to neuroticism. The study utilized both physiological and subjective measures of learned fear, allowing for comparison across domains of fear expression. Eyeblink startle responses indicated that fear conditioning did not take place, with no significant differences in startle response magnitude in the presence of the conditioned and the unconditioned stimulus. Neuroticism was not found to be associated with greater eyeblink startle to either stimulus type. However, subjective fear ratings revealed an increase in fear of the conditioned stimulus following the acquisition phase, and a decrease in fear of the conditioned stimulus following the extinction phase, indicating that fear conditioning did in fact take place. Neuroticism was positively correlated with fear of the conditioned stimulus in the acquisition phase, indicating that more neurotic individuals may in fact acquire fear more readily than less neurotic individuals. Neuroticism was also associated with greater fear of the conditioned stimulus following extinction, suggesting that neurotic individuals may have difficulty learning when a stimulus no longer predicts threat. These findings indicate that neuroticism does impact both acquisition and extinction of conditioned fear, and there is a need for further replication in order to better understand the discrepancies between physiological and subjective measures in assessing fear conditioning

Vicarious Fear Learning: The Role of Empathy

Fear learning can take place indirectly, by observing others, as well as directly through personal experience. This study aimed to determine whether we could detect indirect – sometimes called vicarious – fear learning in the laboratory, and to examine the influence of trait empathy on the robustness of this learning experience. Deficient empathy features prominently in certain externalizing psychopathologies, and fear learning is theoretically implicated in many psychological disorders, but little research has examined the possible connection between the two. In the present study, we first showed participants (N = 80; Mage = 19.1 years, SD = 2.1; 62.5% white) a video of a stranger (called the demonstrator) undergoing a Pavlovian fear conditioning procedure, receiving shocks and loud noises in the context of one of two conditioned stimuli. Next, we presented participants with those same conditioned stimuli. Correlation analyses showed an association between participants’ autonomic nervous system reactivity while observing the demonstrator receive aversive stimuli and their own reactivity when presented with the same conditioned stimulus associated with shock in the video. Associations between trait empathy (measured with the Interpersonal Reactivity Index and the Affective and Cognitive Measure of Empathy) and the strength of vicarious fear learning were generally small. Our results suggest the independence of the emotional response and trait empathy during the observation of someone’s distress

Fear expression is suppressed by tyrosine administration

Animal studies have demonstrated that catecholamines regulate several aspects of fear conditioning. In humans, however, pharmacological manipulations of the catecholaminergic system have been scarce, and their primary focus has been to interfering with catecholaminergic activity after fear acquisition or expression had taken place, using L-Dopa, primarily, as catecholaminergic precursor. Here, we sought to determine if putative increases in presynaptic dopamine and norepinephrine by tyrosine administered before conditioning could affect fear expression. Electrodermal activity (EDA) of 46 healthy participants (24 placebo, 22 tyrosine) was measured in a fear instructed task. Results showed that tyrosine abolished fear expression compared to placebo. Importantly, tyrosine did not affect EDA responses to the aversive stimulus (UCS) or alter participants' mood. Therefore, the effect of tyrosine on fear expression cannot be attributed to these factors. Taken together, these findings provide evidence that the catecholaminergic system influences fear expression in humans

Neural correlates of fear: insights from neuroimaging

Fear anticipates a challenge to one's well-being and is a reaction to the risk of harm. The expression of fear in the individual is a constellation of physiological, behavioral, cognitive, and experiential responses. Fear indicates risk and will guide adaptive behavior, yet fear is also fundamental to the symptomatology of most psychiatric disorders. Neuroimaging studies of normal and abnormal fear in humans extend knowledge gained from animal experiments. Neuroimaging permits the empirical evaluation of theory (emotions as response tendencies, mental states, and valence and arousal dimensions), and improves our understanding of the mechanisms of how fear is controlled by both cognitive processes and bodily states. Within the human brain, fear engages a set of regions that include insula and anterior cingulate cortices, the amygdala, and dorsal brain-stem centers, such as periaqueductal gray matter. This same fear matrix is also implicated in attentional orienting, mental planning, interoceptive mapping, bodily feelings, novelty and motivational learning, behavioral prioritization, and the control of autonomic arousal. The stereotyped expression of fear can thus be viewed as a special construction from combinations of these processes. An important motivator for understanding neural fear mechanisms is the debilitating clinical expression of anxiety. Neuroimaging studies of anxiety patients highlight the role of learning and memory in pathological fear. Posttraumatic stress disorder is further distinguished by impairment in cognitive control and contextual memory. These processes ultimately need to be targeted for symptomatic recovery. Neuroscientific knowledge of fear has broader relevance to understanding human and societal behavior. As yet, only some of the insights into fear, anxiety, and avoidance at the individual level extrapolate to groups and populations and can be meaningfully applied to economics, prejudice, and politics. Fear is ultimately a contagious social emotion

Affective Learning and Psychophysiological Reactivity in Dementia Patients

We examined the association of faces with biographical information that varied in emotional content in patients with Alzheimer's disease and a healthy control group. During two experimental sessions, participants rated neutral male faces on dimensions of hedonic valence and emotional arousal, later paired with fictitious biographical information. Both groups changed their ratings of the faces according to the biographical content. Free recall and recognition were tested in the second session. Patients neither recalled the biographical information nor recognized the faces, whereas the controls did. In addition, psychophysiological measures were taken in response to the face stimuli. Patients showed significant heart rate modulation as a function of their emotion ratings, whereas the controls did not. No correlation of rating changes with skin conductance was found in any group. Results suggest that psychophysiological reactions such as heart rate changes may indicate preserved affective associative learning in dementia patients despite impaired explicit memory

Dynamic competition between large-scale functional networks differentiates fear conditioning and extinction in humans.

The high evolutionary value of learning when to respond to threats or when to inhibit previously learned associations after changing threat contingencies is reflected in dedicated networks in the animal and human brain. Recent evidence further suggests that adaptive learning may be dependent on the dynamic interaction of meta-stable functional brain networks. However, it is still unclear which functional brain networks compete with each other to facilitate associative learning and how changes in threat contingencies affect this competition. The aim of this study was to assess the dynamic competition between large-scale networks related to associative learning in the human brain by combining a repeated differential conditioning and extinction paradigm with independent component analysis of functional magnetic resonance imaging data. The results (i) identify three task-related networks involved in initial and sustained conditioning as well as extinction, and demonstrate that (ii) the two main networks that underlie sustained conditioning and extinction are anti-correlated with each other and (iii) the dynamic competition between these two networks is modulated in response to changes in associative contingencies. These findings provide novel evidence for the view that dynamic competition between large-scale functional networks differentiates fear conditioning from extinction learning in the healthy brain and suggest that dysfunctional network dynamics might contribute to learning-related neuropsychiatric disorders

Electrophysiological Signatures of Fear Conditioning: From Methodological Considerations to Catecholaminergic Mechanisms and Translational Perspectives

Fear conditioning describes a learning mechanism during which a specific stimulus gets associated with an aversive event (i.e., an unconditioned stimulus; US). Thereby, this initially neutral or arbitrary stimulus becomes a so-called “conditioned” stimulus (CS), which elicits a conditioned threat response. Fear extinction refers to the decrease in conditioned threat responses as soon as the CS is repeatedly presented in the absence of the US. While fear conditioning is an important learning model for understanding the etiology and maintenance of anxiety and fear-related disorders, extinction learning is considered to reflect the most important learning process of exposure therapy. Neurophysiological signatures of fear conditioning have been widely studied in rodents, leading to the development of groundbreaking neurobiological models, including brain regions such as the amygdala, insula, and prefrontal areas. These models aim to explain neural mechanisms of threat processing, with the ultimate goal to improve treatment strategies for pathological fear. Recording intracranial electrical activity of single units in animals offers the opportunity to uncover neural processes involved in threat processing with excellent spatial and temporal resolution. A large body of functional magnetic resonance imaging (fMRI) studies have helped to translate this knowledge about the anatomy of fear conditioning into the human realm. fMRI is an imaging technique with a high spatial resolution that is well suited to study slower brain processes. However, the temporal resolution of fMRI is relatively poor. By contrast, electroencephalography (EEG) is a neuroscientific method to capture fast and transient cortical processes. While EEG offers promising opportunities to unravel the speed of neural threat processing, it also provides the possibility to study oscillatory brain activity (e.g., prefrontal theta oscillations). The present thesis contains six research manuscripts, describing fear conditioning studies that mainly applied EEG methods in combination with other central (fMRI) and peripheral (skin conductance, heart rate, and fear-potentiated startle) measures. A special focus of this thesis lies in methodological considerations for EEG fear conditioning research. In addition, catecholaminergic mechanisms are studied, with the ultimate goal of opening up new translational perspectives. Taken together, the present thesis addresses several methodological challenges for neuroscientific (in particular, EEG) fear conditioning research (e.g., appropriate US types and experimental designs, signal-to-noise ratio, simultaneous EEG-fMRI). Furthermore, this thesis gives critical insight into catecholaminergic (noradrenaline and dopamine) mechanisms. A variety of neuroscientific methods (e.g., EEG, fMRI, peripheral physiology, pharmacological manipulation, genetic associations) have been combined, an approach that allowed us (a) to translate knowledge from animal studies to human research, and (b) to stimulate novel clinical directions

Sliding-window analysis tracks fluctuations in amygdala functional connectivity associated with physiological arousal and vigilance during fear conditioning

We evaluated whether sliding-window analysis can reveal functionally relevant brain network dynamics during a well-established fear conditioning paradigm. To this end, we tested if fMRI fluctuations in amygdala functional connectivity (FC) can be related to task-induced changes in physiological arousal and vigilance, as reflected in the skin conductance level (SCL). Thirty-two healthy individuals participated in the study. For the sliding-window analysis we used windows that were shifted by one volume at a time. Amygdala FC was calculated for each of these windows. Simultaneously acquired SCL time series were averaged over time frames that corresponded to the sliding-window FC analysis, which were subsequently associated with the whole-brain seed-based amygdala sliding-window FC using the GLM. Surrogate time series were generated to test whether connectivity dynamics could have occurred by chance. In addition, results were contrasted against static amygdala FC and sliding-window FC of the primary visual cortex, which was chosen as a control seed, while a physio-physiological interaction (PPI) was performed as cross-validation. During periods of increased SCL, the left amygdala became more strongly coupled with the bilateral insula and medial prefrontal cortex, core areas of the salience network. The sliding-window analysis yielded a connectivity pattern that was unlikely to have occurred by chance, was spatially distinct from static amygdala FC and from sliding-window FC of the primary visual cortex, but was highly comparable to that of the PPI analysis. We conclude that sliding-window analysis can reveal functionally relevant fluctuations in connectivity in the context of an externally cued task