Prof. Dr. Martin Bohus

Bohus M, Schmahl C. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP C05: Impact of cognitive and sensory information processing during. 01/2012-12/2015.

The overall aim of this project is to elucidate the role of dysfunctional memory reconsolidation for the stabilization and persistence of traumatic memory and its potential role in the development and aintenance of posttraumatic stress disorder (PTSD). Memory reconsolidation is a putative neuronal, protein-synthesis-dependent process in which the retrieval of a previously consolidated memory returns to a plastic state. During reconsolidation memory can be disrupted, modified or even enhanced. It has recently been demonstrated that oral administration of the β-adrenergic receptor antagonist propranolol during memory reconsolidation in humans erased the behavioral expression of fear memory 24 h later and prevented the return of fear (Kindt et al., 2009). There is ample evidence that after traumatic experience acute memories for these events are repeatedly reactivated for a certain amount of time which allows for the incorporation of new information into trauma related memories and attenuation of the impact of trauma related stimuli. Failures during these automatized reconsolidation processes should lead to over-consolidation of traumatic memories. Since clinical studies have suggested that peri- and posttraumatic dissociation might be a risk factor for the development of PTSD, one could argue that dissociation might impact these automatized reconsolidation processes. During the first funding periods of the SFB we could show on experimental levels that dissociative experience attenuates both sensory processing and learning processes. Hence, one could argue that dissociation attenuates the sensory input driven adaptive memory accommodation during reconsolidation processes which leads to over-consolidation of trauma-associated memories in PTSD. The focus of this study is to test this hypothesis. In a first step we plan i) to examine to what extent sensory information processing during reconsolidation of recently learned fear enhances extinction and whether these effects are comparable to the recently reported effects of propranolol application during reconsolidation (Kindt et al., 2009); ii) to what extent purely cognitive reappraisal during reconsolidation weakens fear memory; and iii) to what extent acute dissociative features during reconsolidation hinder the modification of recently stored memory. We will examine healthy subjects and unmedicated patients with high proneness for dissociation (patients with BPD and complex PTSD). Differential fear conditioning will be applied following an established protocol by Kindt et al. (2009). After the acquisition phase, subjects will go through a reconsolidation paradigm under different conditions including, propranolol, cognitive, sensory and dissociative stimulation. The effects will be tested during extinction and reinstatement. We expect that sensory and cognitive input during reconsolidation weakens initially consolidated memory as well as propranolol. Whereas acute dissociation inhibits these putative sensory and cognitive effects, leading to stabilization of fear memory and enhanced reinstatement.

Bohus M. BMBF - Bundesministerium für Bildung und Forschung 01KR1303A: RELEASE: Behandlung psychosozialer und neuronaler Folgen von interpersoneller Gewalt in der Kindheit bei Erwachsenen. 08/2013-07/2016.

Patienten mit einer Posttraumatischen Belastungsstörung (PTBS) nach interpersonellen Gewalterfahrungen in der Kindheit und Jugend leiden meist unter schweren zusätzlichen psychischen Störungen. Insbesondere die Borderline-Persönlichkeitsstörung (BPS) ist eine häufige Folgestörung und führt zu komplexen Symptombildern. Am Zentralinstitut für Seelische Gesundheit in Mannheim (ZI) wurde mit der Dialektisch Behavioralen Therapie für PTBS (DBT-PTSD) erstmals ein stationäres Behandlungskonzept für dieses häufige Störungsbild entwickelt und evaluiert. Das Hauptziel des Verbundprojektes stellt nun die Überprüfung der Wirksamkeit dieses Behandlungsprogrammes im Vergleich zur Cognitive Processing Therapy (CPT) unter ambulanten Bedingungen dar (Projekt A). Darüber hinaus wird untersucht, welche Faktoren den Erfolg der Therapie maßgeblich beeinflussen (Teilprojekt B). In dem Teilprojekt C werden neuronale Mechanismen der Therapie und deren Auswirkung auf das emotionale Wiedererleben von traumatischen Erinnerungen beforscht. Die Ergebnisse werden im Rahmen von Kongressbeiträgen, Zeitschriftenpublikationen und Medienberichten sowohl der Fachwelt als auch der breiten Öffentlichkeit zugänglich gemacht. Sollte die DBT-PTSD sich als wirksam erweisen werden ärztliche und psychologische Psychotherapeuten in der Behandlung ausgebildet. Die Erfahrungen und das Behandlungskonzept werden auf diese Weise in das Gesundheitssystem disseminiert und kommen so einer großen Gruppe von betroffenen Patienten zugute.

Lis S, Bohus M. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 01 Neurobiological and Psychological Reaction Patterns in Response to Social Rejection in BPD. 08/2015-07/2017.

1 Results of the first funding period The aim of this project was to add to the understanding of the mechanism underlying the pervasive experience of social exclusion in BPD which is assumed to contribute to severe interpersonal problems. In sum, our findings of the first funding period suggest that interpersonal problems in BPD may be primarily linked to an imbalance in the experiences of negative and positive events in every-day life. This is less caused by alterations in the processing of social rejection, but in the processing of positive social cues. In particular, we found that BPD patients experience happy faces as less intense and are less confident during their evaluation. They evaluate particularly positive information referenced to themselves as less positive and this has been related to an internal, negative and global attributional style. They feel less included during positive and neutral social encounters, expect less positive feedback of social co-players, fail to adjust their expectancies particularly in case of positive feedback and react with a drop of cooperative behavior in case of a provocation when previously included by social partners. Brain imaging data suggest that these behavioral data may be linked to a lack in the modulation of the engagement of brain structures depending on the nature of a social encounter. Rejection sensitivity, i.e. a cognitive-affective disposition, which is increased in both acute as well as remitted BPD patients, influenced the intensity of many of these alterations. These distinct maladaptive mechanisms may result in a pervasive disruption of the sense of belonging, feeling different and separated from others, as well as feelings of loneliness and a reduced level of social functioning. 2 New questions and work schedule The findings in funding period 1 emphasize the importance of alterations in the processing of positive social information in BPD. The planned project of funding period serves 2 aims: 1) Transferring these experimental findings into a modular, adaptive computer-assisted therapeutic intervention. This should provide an intensive, cost-efficient training, targeting the improvement of processing positive social information. This program will be evaluated within a randomized controlled trial. 2) Investigating further patho-mechanism in the development of feeling of belonging in BPD. During funding period 1 we had primarily studied features from the receiver perspective (i.e. the perception and evaluation of social rejection and inclusion). In period 2 we will focus on bidirectional processes incl. the sender perspective (i.e. behavioral expression of social signals; the adjustment of social behavior to social context and its consequences for the sense of belonging). We hypothesize, that basal affiliative processes such as behavioral matching, i.e. mimicry and synchronized action, and their interplay with the sensitivity to social reward, the storage of positive social information in memory, and the guidance of action based on positive social experiences are impaired in BPD patients. Effects will be measured by means of overt behavior, psychophysiological parameters (HR, EMG) and its neural correlates (fMRI). Work schedule: For this project, we will collect data from 60 female patients with BPD (age 18-45). For participating in study 2, we will recruit additionally a sample of 40 age, sex and educationally matched female healthy control subjects (age 18-45) and a clinical control group of 40 female patients with social phobia.

DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP Z 2 Central Project 2 - Central Recruitment and Assessment. 08/2015-07/2018.

1 Work program The Central Project is responsible for the coordination and administration of the entire CRU. This comprises the following functions: 1. Organizing central recruitment, assessment, and data handling. 2. Organizing training and inter-rater reliability of diagnosticians. 3. Biomaterial collection 4. Coordinating allocation of funds to the individual projects together with the administration of the CIMH as well as Heidelberg University. 5. Coordinating assignments of the two rotational positions (GEROK-Stellen). 6. Maintaining the internet presence for the CRU. 7. Communicating the goals and results of the CRU to the academic and general public (through the internet and other media) 8. Organizing and coordinating regular meetings of the project leaders and co-workers, scientific retreats, annual international symposia. 9. Allocate start-up funding for young researchers

Bohus M. DFG - Deutsche Forschungsgemeinschaft KFO 256: Mechanisms of Disturbed Emotion Processing in Borderline Personality Disorder. 01/2012-12/2014.

Borderline personality disorder (BPD) is a highly prevalent and complex mental disorder that often takes a chronic and severely debilitating course if left untreated. Current theories view dysfunctions in emotion processing, social interaction, and mpulsivity as core mechanism of BPD. This often leads to prototypical behavioral patterns such as suicide attempts, non-suicidal self-injury, high-risk behavior, and impulsive aggression. Most of these patterns can typically be traced back to mid-adolescence. Recent research on psychological and neural mechanisms of BPD points towards an interplay between dysfunctional information processing, structural and functional impairments of fronto-limbic circuits, and learned maladaptive behavior. However, compared to other mental disorders of this importance, scientific knowledge on BPD is relatively sparse. Reasons include study samples that are small, heterogeneous, and often medicated; and a paucity of studies that include clinical controls. Also lacking are experimental data on remitted BPD patients, which might allow for the identification of state-independent psychobiological characteristics that could be accounted for by endophenotypes. These limitations impede both the identification of genetic markers and the development of more specific pharmacologic and psychotherapeutic treatment strategies. The Clinical Research Unit (CRU) at Heidelberg University will join the competences of their members which include clinical and psychopathological competence in both adult and adolescent BPD, expertise in neuropsychology, neuroimaging, genetics, and translational neuroscience. The aim is to further characterize subcomponents of dysfunctional emotion processing and social interaction in BPD and to elucidate their neural underpinnings. This should facilitate the development of specifically tailored psychotherapeutic interventions on one level, and provide the basis for further research on a molecular level on another. To this end, the CRU´s central project will carefully characterize and define the phenotypes of a total of 270 unmedicated patients with BPD, including current, remitted, and adolescent populations. The central project will recruit the patients needed in 6 closely related individual projects (IP1-IP6) that will focus on the following psychological and neural mechanisms: i) rejection hypersensitivity and its consequences for social cooperation, ii) dysfunctional responses to pro-social and aversive social stimuli, iii) deficient capability in trust and coaxing, iv) insufficient sensory integration and its impact on dissociation, v) dysfunctional processing of emotional stimuli and neurofeedback training, vi) self-injurious behavior as a form of dysfunctional emotion regulation, and vii) functional and structural connectivity related to disturbed emotion processing. These 6 projects, will be complemented by 3 associated projects. These associated projects (AP1-AP3) will focus on impulsivity, development of a new treatment, and development of an animal model.

Bohus M. DFG - Deutsche Forschungsgemeinschaft BO 1487/11-1: KFO 256 TP 1: Neurobiological and Psychological Reaction Patterns in Response to Social Rejection in BPD. 01/2012-12/2014.

Bohus M. DFG - Deutsche Forschungsgemeinschaft BO 1487/13-1: KFO 256 CP 1: Coordination, Administration, and Public Relations of the Clinical Research Unit in BPD. 01/2012-12/2014.

Bohus M, Rietschel M. DFG - Deutsche Forschungsgemeinschaft BO 1487/12-1: KFO 256 CP 2: Central Recruitment and Assessment. 01/2012-12/2014.

Bohus M. Deutsche José Carreras Leukämie-Stiftung e.V. DJCLS R 10/42 pf: Effect of a 1-year individually adapted physical exercise program on survival rates after allogeneic hematopoietic stem cell transplantation. 01/2011-12/2013.

Bohus M. : KFO 256 AP 2: Interpersonal Effectiveness Skills-Training: Development and Evaluation of a New Psychotherapy Tool. 01/2012-12/2014.