Final Report Summary - EMOLEARN (Emotional learning and extinction: integration of central and peripheral neural correlates.) Main scientific highlights and research achievements are published in four peer reviewed articles attached:1) MultiCS conditioning is an affective associative learning paradigm, in which affective categories consist of many similar and complex stimuli. Comparing visual processing before and after learning, recent MultiCS conditioning studies using time sensitive magnetoencephalography (MEG) revealed enhanced activation of prefrontal cortex (PFC) regions towards emotionally paired versus neutral stimuli already during short-latency processing stages (i.e. 50 to 80 ms after stimulus onset). The present study aimed at showing that this rapid differential activation develops as a function of the acquisition and not the extinction of the emotional meaning associated with affectively paired stimuli. MEG data of a MultiCS conditioning study were analyzed with respect to rapid changes in PFC activation towards aversively (electric shock) paired and unpaired faces that occurred during the learning of stimulus-reinforcer contingencies. Analyses revealed an increased PFC activation towards paired stimuli during 50 to 80 ms already during the acquisition of contingencies, which emerged after a single pairing with the electric shock. Corresponding changes in stimulus valence could be observed in ratings of hedonic valence, although participants did not seem to be aware of contingencies. These results suggest rapid formation and access of emotional stimulus meaning in the PFC as well as a great capacity for adaptive and highly resolving learning in the brain under challenging circumstances.2) Relative to healthy controls, anxiety-disorder patients show anomalies in classical conditioning that may either result from, or provide a risk factor for, clinically relevant anxiety. Here, we investigated whether healthy participants with enhanced anxiety vulnerability show abnormalities in a challenging affective conditioning paradigm, in which multiple stimulus-reinforcer associations had to be acquired in few learning trials only. Forty-seven high and low trait-anxious females underwent MultiCS conditioning, in which 52 different neutral faces (CS+) were paired with an aversive noise (US), while further 52 faces (CS-) remained unpaired. Emotional learning was assessed via evaluative (rating) and behavioral (dot-probe, contingency report) as well as neurophysiological (magnetoencephalography) measures acquired before, during, and after learning. High and low trait anxious groups did not differ in evaluative ratings or motor-response priming after conditioning. However, the high trait-anxious group was better than the low trait-anxious group at reporting CS+/US contingencies after conditioning and showed an enhanced prefrontal cortex activation towards CS+ in the M1 (i.e. 80 to 117 ms) and M170 time-interval (i.e. 140 to 160 ms) during acquisition. These alterations in MultiCS conditioning observed in elevated trait anxiety are consistent with theories of enhanced conditionability in anxiety vulnerability. Furthermore, they point towards increased threat monitoring and detection in highly trait-anxious females that could be mediated by alterations in visual working memory.3) Several challenges make it difficult to simultaneously investigate central and autonomous nervous system correlates of conditioned stimulus (CS) processing in classical conditioning paradigms. Such challenges include, for example, the discrepant requirements of electroencephalography (EEG) and electrodermal activity (EDA) recordings with regard to multiple repetitions of conditions and sufficient trial duration. Here, we propose a MultiCS conditioning set-up, in which we increased the number of CSs, decreased the number of learning trials, and used trials of short and long durations for meeting requirements of simultaneous EEG-EDA recording in a differential aversive conditioning task. Forty-eight participants underwent MultiCS conditioning, in which four neutral faces (CS+) were paired four times each with aversive electric stimulation (UCS) during acquisition, while four different neutral faces (CS-) remained unpaired. When comparing after relative to before learning measurements, EEG revealed an enhanced centro-posterior positivity to CS+ vs. CS- during 368 to 600 ms, and subjective 33 ratings indicated CS+ to be less pleasant and more arousing than CS-. Furthermore, changes in CS valence and arousal were strong enough to bias subjective ratings when faces of CS+/CS- identity were displayed with different emotional expression (happy, angry) in a post-experimental behavioral task. In contrast to a persistent neural and evaluative CS+/CS differentiation that sustained multiple unreinforced CS presentations, electrodermal differentiation was rapidly extinguished. Current results suggest that MultiCS conditioning provides a promising paradigm for investigating pre-post learning changes under minimal influences of extinction and overlearning of simple stimulus features. Our data also revealed methodological pitfalls, such as the possibility of occurring artifacts when combining different acquisition systems for central and peripheral psychophysiological measures.These research achievements provided the basis for first successful clinical application of the newly developed Multi-CS conditioning paradigm in patients suffering from schizophrenia:4) Abnormalities in the perception and identification of emotions have frequently been reported in schizophrenia. Hemodynamic neuroimaging studies demonstrated functional abnormalities in cortical and subcortical brain circuits essentially involved in normal affective processing but the temporal dynamics of abnormal emotion processing in schizophrenia remain largely elusive. To investigate this issue, we recorded early auditory evoked field components by means of time-sensitive whole-head magnetoencephalography in response to a multitude of emotion-associated tones in seventeen patients with schizophrenia and seventeen healthy, matched controls. Forty-two ultra-short, click-like tones (conditioned stimuli; CS) acquired emotional meaning through a novel affective associative learning procedure, MultiCS conditioning, by pairing each CS three times with either an emotionally arousing pleasant or unpleasant, or a neutral auditory scene. As expected, differential affect-specific modulation in patients vs. controls was evident starting at the auditory N1m onset latency around 70 ms and extending until 230 ms after tone-onset. Distributed neural source estimation localized this difference effect to the right prefrontal cortex. The present finding suggests impairments in the prioritization of emotionally salient vs. non-relevant stimuli in patients with schizophrenia. Dysfunctions in higher cognitive processes and behavior in schizophrenia might therefore reflect dysfunctions on fundamental, early auditory emotion processing stages.1) Rehbein M.A. Steinberg C., Wessing I., Pastor M.C. Zwitserlood P., Keuper K., & Junghöfer M. (2014). Rapid Plasticity in the Prefrontal Cortex during Affective Associative Learning. PLoS One. 9(10):e110720. 2) Rehbein M.A. Wessing I., Zwitserlood P., Steinberg Ch., Eden A, Dobel Ch, & Junghöfer M. (2015) Rapid prefrontal cortex activation towards aversively paired faces and enhanced contingency detection are observed in high trait anxiety under challenging conditions. Frontiers in Behavioral Neuroscience. 9:1553) Pastor M.C. Rehbein M.A. Junghöfer M., Poy R., López R., & Moltó J. (2015). Facing challenges in differential classical conditioning research: Benefits of a hybrid design for simultaneous electrodermal and electroencephalographic recording. Frontiers in Human Neuroscience. 9:3364) Junghöfer M, Bröckelmann AK, Küppers K, Ohrmann P, Pedersen A. (2015). Abnormal, affect-specific modulatory effects on early auditory processing in schizophrenia: magnetoencephalographic evidence. Schizophrenia Research 161(2-3):308-13.