Associations between childhood maltreatment and responding to signals of threat and safety in a fear conditioning paradigm

In project A1, we aim to investigate how childhood adversity gets ‚under the skin‘ by investigating the neuro-physiological mechanisms underlying response differences to signals of threat and safety in individuals exposed and not exposed to early life adversity. To this end, we use state of the art functional and structural imaging in combination with defensive startle responding and measures of physiological arousal and endocrine stress responding (cortisol in hair and saliva) in a fear conditionig and generalization paradigm. Together with projects C1 and C2, we also follow a long-term perspective and assess symptom scores recurrently for a 72 month period to explore data driven subgroups and their link to responding in a fear conditioning paradigm in a large pooled sample.


Opioid regulation of the consolidation of conditioned fear

Emotional memories induce a complex neurotransmitter response that transforms labile learning experience into persistent memories. Project A2 aims to illuminate the underlying neuropsychopharmacological mechanisms how emotional memories become less persistent.
To this end, this project will conduct psychopharmacological, as well as neuropsychopharmacological fMRI experiments to examine the impact of the opioid and noradrenaline system on conditioned fear in humans.
This project is closely linked to other project that investigate noradrenergic arousal (B1, B2), stress (B2, B3), and the opioid system (A3), as well as fear conditioning in healthy and clinical populations (A1, C1, C2).


Representation of aversive cues predicting appetitive outcomes

In everyday life, there are many instances in which an aversive event predicts a positive outcome. Yet, how the prospect of a reward linked to a negatively valenced stimulus can change the responding to and representation of the aversive stimulus is unknown. This project aims to establish a classical conditioning paradigm in which a negatively valenced conditioned stimulus (CS) differentially predicts a positively valenced US. This paradigm in combination with computational modelling will allow us to investigate learning related effects at the autonomic (EDA) and neurobiological level (fMRI). With respect to model based fMRI, we will focus on multivariate methods such as representational similarity analysis5 to characterize dynamically changing representations of the CS as a function of learning.

We expect that the pairing with a reward will lead to a decrease of the unpleasantness rating and EDA response to the paired CS. With respect to multivariate neural representation of each CS, we expect them to differ initially in the insula and mPFC, but over time the representations of the aversive CSs in these regions should get more similar to the pattern evoked by the rewarding US. As previous studies have suggested a role of endogenous opioids in signaling hedonic aspects of reward, we expect that the pattern changes described above can be blocked by Naloxone.


Control of memory formation and memory-based decision-making by brainstem arousal systems

Mounting evidence points to a strong impact of brainstem arousal systems on memory mechanisms (encoding and recall) operating in the cerebral cortex. Unraveling this brainstem-cortical interplay is critical for advancing our understanding of healthy memory and of psychiatric disorders. In this project, we plan to uncover the causal effect of arousal signals from the brainstem on memory formation and memory-based decisions. This will be afforded by an integrated application of pupillometry, behavioral modeling, brainstem fMRI, and magnetoencephalography (MEG) in healthy human participants. We will use novel experimental designs to manipulate the responses of brainstem arousal systems, precisely in time, and quantify the effect on memory processes at a high level of mechanistic detail.


How stressful encounters bias memory for surrounding events

In project B2, we aim to elucidate the cognitive and neural mechanisms underlying stress-induced biases in the memory for events surrounding the stressful episode. To this end, we will combine, in healthy participants, a novel memory paradigm probing predictive coding-related changes in memory formation with an experimental stress manipulation, fMRI and state-of-the art multivariate analyses of human brain imaging data (e.g. representational similarity analysis). Further, this project will include pupillometry as well as autonomic and endocrine stress response measurements.


Linking memories under stress

Project B3 will examine how and through which mechanisms acute stress may affect the linking of overlapping events. For this purpose, we will employ an associative inference task, in combination with an established experimental stress induction, fMRI and multivarite pattern classification. This project will be conducted in close collaboration with colleagues from the Donders Insitute of Brain, Cognition and Behaviour (Nijmegen, The Netherlands) and the University of Texas at Austin.


Fear conditioning in obsessive-compulsive disorder, participants at risk and healthy controls

Project C1 examines the role of fear and safety learning in the etiology of obsessive-compulsive disorder (OCD), a debilitating mental disorder characterized by intrusive thoughts and repetitive compulsions. We address the following questions: Are altered fear and safety learning the cause or the consequence of symptoms? Can we predict symptom development and disorder course from altered learning processes? What cognitive and neural mechanisms underlie observed changes in fear and safety learning?
To this end, we use EEG and peripheral physiological markers to examine fear learning and extinction in patients with OCD, participants at increased risk of developing OCD (unaffected relatives), and healthy participants. The predictive value of fear conditioning for symptom development is examined with recurrent follow-up measures of symptoms.


Fear acquisition and extinction learning and transition to psychosis

In project C2 we aim to identify aberrancies in fear acquisition and extinction associated with psychotic liability. We will focus on participants with clinical high risk of psychosis and use an established differential fear conditioning paradigm in close collaboration with projects A1 and C1 and a novel fear conditioning paradigm, in which the unconditioned stimulus is aversive imagery. We will also test whether altered psychophysiological and neural (EEG) indicators of fear learning can be accounted for by baseline-differences in neurocognition, arousal and psycho-social vulnerability and whether they predict transition to DSM-5 psychotic disorder by a 72-month follow-up.


Systematic Training of Cognitive Processes in Patients with Posttraumatic Stress Disorder (PTSD)

In project C3, we aim to study cognitive processes in patients with PTSD. We will develop and systematically test a video-game based training intervention in a clinical sample by use of a pre-post-test design. Behavioural and structural as well as functional magnetic resonance imaging assessments will be done before and after a six-week training period. Two clinical follow-ups will be conducted after six and twelve months to investigate the training effects in comparison to a control group.


Effects of stress on event memory in everyday life in healthy and (sub)clinical populations

Within the scope of C4 we aim to understand how stress can alter memory processes and whether exposure to nature can buffer these effects. We plan to conduct a laboratory functional MRI study using a scene encoding task where we vary the content of nature depicted in the stimulus material and the timepoint of the administration of the stressor. Moreover an ecological momentary assessment (EMA) study will be conducted where stressors will be applied via a smartphone and photos will be taken in the daily life of participants to test, whether the effects observed in the laboratory study extend into real life.