Emotional learning and its impact on back pain chronicity

Chronic back pain is a worldwide health issue. Patients suffering from chronic pain often live in a vicious cycle of disability and distress. Neuroimaging studies have already shown that the brain changes in its structure and function once the pain has become chronic. However, it is not well understood, whether these changes are also predictors of pain chronicity and which are the relevant underlying mechanisms in this process. Emotional learning may play an important role in this context. The investigation of functional and structural changes in the brain concomitant with associated emotional learning mechanisms might help to identify risk and resilience factors in the transition from acute to chronic back pain. The aim of this thesis is to investigate appetitive and aversive learning mechanisms in patients with subacute back pain and chronic back pain, compared to a group of healthy controls, using functional magnetic resonance imaging. Emotional learning-related brain mechanisms seemed to be maladaptive in patients with back pain affecting the subacute and chronic back pain stage differently. This was indicated by a weaker activation of the hippocampus and the amygdala, but stronger activation in the parietal operculum during appetitive learning in subacute pain patients when compared to healthy controls. Chronic back pain patients showed weaker activations in the nucleus accumbens and the hippocampus besides stronger activation seen in the posterior cingulate cortex in comparison to the healthy control sample. Both pain samples showed a shift away from reward-related brain regions towards pain-related brain areas during appetitive learning. Subacute and chronic back pain patients revealed enhanced aversive learning responses in comparison to healthy controls with a strong impact of the limbic system on learning-related brain activation. Moreover, emotional learning responses in subacute back pain patients seemed to be driven by responses to affective sensory stimulation in the orbitofrontal cortex. A brain region which is thought to process reward-related information, such as the orbitofrontal cortex, influenced learning in the early subacute pain stage, irrespective of the tested learning mechanism. These findings suggest that emotional learning might be an important mechanism causing the transition from acute to chronic pain, indicated by neuroplastic changes in the brain that may serve as predictive markers of pain chronicity

Explicit and Implicit Processes in Human Aversive Conditioning

The ability to adapt to a changing environment is central to an organism’s success. The process of associating two stimuli (as in associative conditioning) requires very little in the way of neural machinery. In fact, organisms with only a few hundred neurons show conditioning that is specific to an associated cue. This type of learning is commonly referred to as implicit learning. The learning can be performed in the absence of the subject’s ability to describe it. One example of learning that is thought to be implicit is delay conditioning. Delay conditioning consists of a single cue (a tone, for example) that starts before, and then overlaps with, an outcome (like a pain stimulus). In addition to associating sensory cues, humans routinely link abstract concepts with an outcome. This more complex learning is often described as explicit since subjects are able to describe the link between the stimulus and outcome. An example of conditioning that requires this type of knowledge is trace conditioning. Trace conditioning includes a separation of a few seconds between the cue and outcome. Explicit learning is often proposed to involve a separate system, but the degree of separation between implicit associations and explicit learning is still debated. We describe aversive conditioning experiments in human subjects used to study the degree of interaction that takes place between explicit and implicit systems. We do this in three ways. First, if a higher order task (in this case a working memory task) is performed during conditioning, it reduces not only explicit learning but also implicit learning. Second, we describe the area of the brain involved in explicit learning during conditioning and confirm that it is active during both trace and delay conditioning. Third, using functional magnetic resonance imaging (fMRI), we describe hemodynamic activity changes in perceptual areas of the brain that occur during delay conditioning and persist after the learned association has faded. From these studies, we conclude that there is a strong interaction between explicit and implicit learning systems, with one often directly changing the function of the other.</p

Neural Responses During Trace Conditioning with Face and Non-Face Stimuli Recorded with Magnetoencephalography

During fear conditioning a subject is presented with an initially innocuous stimulus like an image (conditioned stimulus; CS) that predicts an aversive outcome like a mild electric shock (unconditioned stimulus; UCS). Subjects rapidly learn that the CS predicts the UCS, and show autonomic fear responses (CRs) during the presentation of the CS. When the CS and the UCS coterminate, as is the case for delay conditioning, individuals can acquire CRs even if they are unable to predict the occurrence of the UCS. However when there is a temporal gap between the CS and the UCS, CR expression is typically dependent upon explicit awareness of the CS-UCS pairing. Research with non-human animals suggests that both the hippocampus and the prefrontal cortex are needed for trace but not delay fear conditioning, and that communication between these areas may help to maintain the CS during the trace interval. We tested this hypothesis by exposing subjects to differential delay and trace fear conditioning while we recorded their brain activity with magnetoencephalography. Faces and houses served as CSs and an aversive electrical stimulation served as the UCS. As predicted, subjects show evidence of conditioning on both implicit and explicit measures. In addition, there is a learning related increase in theta coherence between the left parahippocampal gyrus and several frontal and parietal cortical regions for trace but not delay conditioning. These results suggest that trace conditioning recruits a network of cortical regions, and that the activity of these regions is coordinated by the medial temporal lobe

The Effects of Acute Stress Exposure on Neural Correlates of Pavlovian Conditioning with Monetary Gains and Losses

Pavlovian conditioning involves the association of an inherently neutral stimulus with an appetitive or aversive outcome, such that the neutral stimulus itself acquires reinforcing properties. Across species, this type of learning has been shown to involve subcortical brain regions such as the striatum and the amygdala. It is less clear, however, how the neural circuitry involved in the acquisition of Pavlovian contingencies in humans, particularly in the striatum, is affected by acute stress. In the current study, we investigate the effect of acute stress exposure on Pavlovian conditioning using monetary reinforcers. Participants underwent a partial reinforcement conditioning procedure in which neutral stimuli were paired with high and low magnitude monetary gains and losses. A between-subjects design was used, such that half of the participants were exposed to cold stress while the remaining participants were exposed to a no stress control procedure. Cortisol measurements and subjective ratings were used as measures of stress. We observed an interaction between stress, valence, and magnitude in the ventral striatum, with the peak in the putamen. More specifically, the stress group exhibited an increased sensitivity to magnitude in the gain domain. This effect was driven by those participants who experienced a larger increase in circulating cortisol levels in response to the stress manipulation. Taken together, these results suggest that acute stress can lead to individual differences in circulating cortisol levels which influence the striatum during Pavlovian conditioning with monetary reinforcers

Context conditioning and extinction in humans: differential contribution of the hippocampus, amygdala and prefrontal cortex

Functional magnetic resonance imaging was used to investigate the role of the hippocampus, amygdala and medial prefrontal cortex (mPFC) in a contextual conditioning and extinction paradigm provoking anxiety. Twenty-one healthy persons participated in a differential context conditioning procedure with two different background colours as contexts. During acquisition increased activity to the conditioned stimulus (CS+) relative to the CS− was found in the left hippocampus and anterior cingulate cortex (ACC). The amygdala, insula and inferior frontal cortex were differentially active during late acquisition. Extinction was accompanied by enhanced activation to CS+ vs. CS− in the dorsal anterior cingulate cortex (dACC). The results are in accordance with animal studies and provide evidence for the important role of the hippocampus in contextual learning in humans. Connectivity analyses revealed correlated activity between the left posterior hippocampus and dACC (BA32) during early acquisition and the dACC, left posterior hippocampus and right amygdala during extinction. These data are consistent with theoretical models that propose an inhibitory effect of the mPFC on the amygdala. The interaction of the mPFC with the hippocampus may reflect the context-specificity of extinction learning

Anxiety, inhibition and the prefrontal cortex

This dissertation investigates the impact of trait anxiety and anxiety sensitivity on emotional and behavioural inhibition in healthy subjects. An aversive fear-conditioning and extinction design was employed to study the influence of trait anxiety on the neurobiology of emotional inhibition using fMRI. A Go/ Nogo-task was selected to examine the impact of trait anxiety and anxiety sensitivity on the electrophysiology of response inhibition using EEG. Our findings emphasize the role of the prefrontal cortex and the ACC in inhibition and anxiety. In the first experiment, trait anxiety was related to impaired fear extinction. Neurobiologically, hypo-activation of the PFC and hyper-activation of the amygdala have been observed. The second experiment yielded enhanced response inhibition and anxiety-related hyper-activation of the PFC. Thus, anxiety is related to deficits in behavioural and emotional inhibition

Changes in Resting-State Functional Connectivity Following Delay and Trace Fear Conditioning Acquisition and Extinction

Consolidation is the process of stabilizing a recently acquired memory into a more permanent or durable form. Several studies with laboratory animals have uncovered valuable information about the process of consolidation, but less is known about the process of consolidation in healthy humans. The current study examined the consolidation of emotional memories in different brain circuits in healthy humans using resting-state fMRI. We used the acquisition and extinction of two variations of Pavlovian fear conditioning, delay and trace, which rely on slightly different circuits to examine changes in functional connectivity related to a general fear learning process and also to examine how these changes may differ in these circuits. We found that the acquisition of delay and trace fear conditioning involves similar circuitry including the amygdala, but that trace conditioning involves the addition of a few more brain regions to the general circuit including the hippocampus. Twenty-four hours following acquisition there was an increase in functional connectivity between the amygdala and several other brain areas including the hippocampus and medial prefrontal cortex for both the delay and trace groups suggesting that these changes reflect the consolidation of a general fear memory. We also observed changes in connectivity that were specific to the trace group in brain regions thought to be specifically involved in trace conditioning including the medial prefrontal cortex and the retrosplenial cortex. By seven days after acquisition most of the changes in connectivity had returned to baseline. Extinction data revealed that the ventromedial prefrontal cortex was involved in forming this inhibitory memory and that connectivity between the amygdala and a region of ventromedial prefrontal cortex increased for the trace group following extinction. These results suggest that consolidation can be measured in healthy humans using resting-state fMRI and that these processes occur in the same circuits that are responsible during training

Extending the concept of emotion regulation with model-based fMRI

Effective emotion regulation is essential for our social and emotional well-being. Yet, the concept of emotion regulation, as it is conventionally regarded in the field, does not take important aspects of emotions and emotion regulation into account. The overarching aim of the current thesis was to include such missing aspects and thereby expand the concept of emotion regulation. The expansion occurred in two directions: firstly, the definition of emotion within the field of emotion regulation was widened to include the motivational aspect of emotions in terms of value-based prediction errors and their neural implementation; and secondly, an underestimated type of emotion regulation – the social emotion regulation – and its neural underpinnings were investigated. Projects 1 and 2 of the current thesis expand the emotion part of emotion regulation. Project 1 investigated whether emotion regulation affects not only emotional response-related brain activity but also influences aversive prediction error-related activity, i.e., the motivation-related brain signal. We found that self- initiated reappraisal, a type of cognitive emotion regulation, indeed affected prediction error-related activity, such that this activity was enhanced in the ventral tegmental area, ventral striatum, insula and hippocampus, possibly via a prefrontal-tegmental pathway. Project 2 further examined the way emotion regulation affects emotions and prediction errors, by testing whether self- initiated reappraisal directly targets the brain network for motivated behaviour previously outlined by animal studies. We found that superior (in contrast to inferior) regulators affected the balance of competing influences of ventral striatal afferents on striatal aversive prediction error signals; they reduced the impact of subcortical striatal afferents (i.e., hippocampus, amygdala and ventral tegmental area), while keeping the influence of the prefrontal cortex on ventral striatal prediction errors constant. Inferior regulators, on the other hand, failed to supress subcortical inputs into the ventral striatum and instead counterproductively reduced the prefrontal influence on ventral striatal prediction error signals. Projects 3 and 4 of the thesis extend the regulation part of emotion regulation. Project 3 explored the neural correlates of social cognitive emotion regulation, specifically reappraisal, and directly compared them with those of self-initiated reappraisal. We found that regions of the anterior, the medial parietal, and the lateral temporo-parietal default mode network were specifically involved in social emotion regulation, and that social regulation success and the default mode network involvement during regulation were related to participants’ attachment security scores. Project 4 investigated social emotion modulation and its impact on two distinct types of emotional brain activity – emotional response- and aversive prediction error-related activity. We found – for the simple contrast of being with somebody versus being alone – a three-fold dissociation between signal types and insula subregions, including left and right anterior and posterior insula parts. Social emotion modulation reduced aversive stimulus-related activity in the posterior insula, while simultaneously increasing aversive prediction error-related activity in the anterior insula. Furthermore, the social effect on prediction error-related activity was positively associated with aversive learning in the right, but negatively in the left anterior insula. Altogether, by expanding the concept of emotion regulation, projects of the current thesis provide new insights into both the effects and the neural underpinnings of three distinct emotion regulation types. Considering that problems in both intrapersonal emotion regulation and social interaction are linked to affective disorders, our findings might contribute to a better understanding of these disorders and the disorder-specific emotional and social impairments

Contextual Modulation of Associative Learning and the Role of Resting State Brain Activity in Posttraumatic Stress Disorder

In the present dissertation we addressed neuronal changes in PTSD using an activationbasedand a resting state-based approach with a special focus on brain areas involved in abnormal activation in PTSD such as amygdala, hippocampus, ventromedial prefrontalcortex (vmPFC), dorsal anterior cingulate cortex (dACC) and insula. Our attention was directed to the mechanisms mediating increased return of fear and the association of PTSD symptoms with aberrant brain activity as well as aberrant resting state connectivity. In both studies we compared PTSD patients with trauma-exposed but unaffected controls (non-PTSD) and trauma-naïve healthy controls (HC). In the first study, subjects underwent an ABC fear conditioning and extinction procedure, where two CSs were presented in front of virtual reality scenes. One of them (CS+) was paired with a slightly painful electrical stimulation (US) during acquisition, whereas the other one was never paired with the US (CS-). During extinction, there were no CS-US pairings. After acquisition (context A) and extinction (context B), the participants were brought to a novel context C and again confronted with the CSs. Selfreports, skin conductance responses (SCR) and functional magnetic resonance imaging (fMRI) were measured simultaneously. We found elevated return of fear in the PTSD patients indicated by larger differential SCR compared to non-PTSD and HC and larger differential amygdala and hippocampus activity compared to HC. Increased amygdala activation was positively correlated with numbing and vmPFC activity was positively correlated with behavioral avoidance even though there were no functional group differences in this region of interest. Additionally, PTSD patients failed to appropriately reduce subjective arousal to the CS- over the course of the experiment and to the CS+ during extinction. Taken together, the results of study 1 support the hypothesis that PTSD is characterized by aberrant activity within regions of the neurocircuitry model, which leads to deficient extinction maintenance. Furthermore, our data confirm a general inability of PTSD patients to correctly identify safety signals and modulate fear responses based on this information. Such dysfunctional mechanisms seem to contribute to PTSD symptoms and represent a probable cause for relapse, whereas resilient subjects appear to benefit from protective mechanisms. In the second study, subjects underwent a resting state scan and functional connectivity was analyzed using an amygdala seed and independent component analysis (ICA) as well as correlations with symptom severity. The seed-based approach revealed increased left amygdala – the left insula coupling in PTSD versus nonPTSD, which positively correlated with re-experiencing intensity. Compared to HC, both trauma experienced groups showed higher positive correlations of the left amygdala and the right putamen as well as the right insula. The ICA did not reveal any group differences, i.e. in DMN connectivity. In summary, study 2 indicates that altered amygdala-insula coupling and decreased amygdala-putamen coupling, but not DMN connectivity, contribute to the pathophysiology of PTSD. Hyperconnectivity between the left amygdala and the left insula differentiated patients from resilient subjects and was linked to re-experiencing intensity. This result suggests that a stronger functional link between somatic sensations and emotional appraisal might lead to increased anticipation of negative events in PTSD, which potentially explains characteristic symptoms such as hyperarousal and negative alterations in mood and cognition