Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry

The focus will be on the influences of a provocative context on social threat processing in AMD under different testosterone levels. Specifically, the project aims to analyze the modulating function of context under testosterone application versus suppression on threat sensitivity in healthy controls as well as patient groups. Additionally, we will determine the influence of endogenous hormone variations (testosterone, oxytocin, estrogen and cortisol) on NVS in high versus low aggressive patients in a large group of patients recruited in Q01. With this sample, we will try to identify multidimensional biosignatures based on hormonal levels in combination with fMRI measures of amygdala and amygdala-prefrontal connectivity, NVS measures by questionnaires, aggression measures and psychopathological data.

The neural and neurochemical patterns of acute threat as modulators of aggression in BPD will be investigated in this project. The modulation of aggressive responses under acute threat is induced by the threat-of-shock paradigm. The main translational research question is if and how aggressive responses are modulated by threat, and which neurofunctional and neurochemical patterns underlie these responses during safe and threat conditions. MR spectroscopy will be used in patients to assess glutamate and GABA levels. In a further translational approach, the least and the most aggressive/impulsive recombinant inbred mouse lines identified in C01 in Frankfurt will be tested in Mannheim with animal MR spectroscopy at 9.4T to determine the relationship between glutamate, GABA, impulsivity, and aggression in these mouse lines as well as in comparable brain regions assessing neurofunctional and neurochemical patterns.

We make use of threat-related chemosensory stimuli, namely body odor, acquired during aggressive behavior (boxing) and unconsciously perceived, to investigate heightened amygdala responses to threat stimuli in aggressive patients. Body odors have the major advantage of being directly projected into the amygdala, circumventing cortical preprocessing, thereby enabling the differentiation of mechanisms between bottom-up altered limbic processing and top-down modulated altered cognitive evaluation. We investigate the potential of such body odors to bias responses to ambiguous visual social cues towards threat and their effects during peripersonal space (PPS) violation where they may be especially relevant.

The project employs fMRI and functional near-infrared spectroscopy (fNIRS) hyperscanning techniques to explore how brain-to-brain synchrony and dynamic processes within peer dyads facilitate or inhibit aggressive behavior under diverse levels of provocation in adolescent patients and controls. In two fully interactive tasks, we will probe aggressive behavior towards a task partner, and quantify the building of interpersonal trust/distrust applying a social interaction and economic exchange paradigm. These paradigms will be employed within dyads in fMRI hyperscanning settings and extended by group-based fNIRS methods in triads to study effects of peers, social exclusion, and coalitions on aggressive behavior in semi-naturalistic interactions. Between-brain neural synchrony will be computed and related to everyday social experiences and individual predispositions to identify markers for the prediction of aggressive behavior.

Beta-hydroxy-butyrate (BHB), a ketone body, is negatively associated with aggressive behavior. BHB is a metabolite and an active signaling substrate involved in epigenetic regulation of e.g., neurotrophic factor genes in the brain. Of the three main ketone bodies, acetone, acetoacetate and BHB, acetone is a very volatile compound, mainly eliminated through respiration, thus can be measured non-invasively in breath. A reduction of acetone in breath has been found to highly correlate with BHB in blood and be associated with symptom severity in schizophrenia (Jiang et al. 2022). Using MR spectroscopy, A08 aims to (1) identify whether acetone and other volatile organic compounds in breath are associated with aggression and acute threat processing in mental disorders and (2) to examine whether these breath markers are associated with direct metabolic brain correlates (like BHB, glutamate) and with the brain-derived neurotrophic factor (BDNF) levels in plasma. In a translational approach, (3) we will test if supplementation of BHB reduces aggressive behavior in mice.

TDCS will be used as an interventional tool to decrease aggression. Using a simultaneous tDCS – fMRI approach, the project aims to enhance cognitive control by repeated prefrontal brain stimulation, investigating its effect on aggression. In addition to gauging tDCS responsivity, identifying the role of individual factors such as genetic profiles in aggression will be a particular focus of this project. By examining brain activity at multiple time points (e.g., before, during multiple stimulation sessions and after tDCS), it will add to the understanding of mechanisms underlying neural tDCS effects and help to identify individual factors that predict responsiveness to the stimulation. To determine the therapeutic potential, we will include psychiatric patients with substance use problems, a group of criminal, violent offenders, and healthy matched controls.

This project aims to identify cognitive and emotion control deficits in the context of negative valence and threat interference and their association with ACE in young offenders. Complementary to other projects, this project will focus on a group of young people defined by their propensity to aggression showing at the same time more severe psychopathologies. In a series of studies using multimodal imaging (EEG-fMRI, EEG-sMRI) in combination with naturalistic longitudinal follow-up (ecological momentary assessment (EMA)) B02 will identify the neural mechanisms and predictors of self-regulation deficits as a putative common developmental pathway for both, aggressive behavior, and psychopathology. Additionally, B02 will seek to causally confirm neural network mechanisms of inhibitory control and emotion regulation deficits as the basis of aggressive behavior and associated psychopathology by real-time EEG-triggered TMS-stimulation in young offenders.

Focus on the neural correlates of characterizing cognitive control deficits during conflict situations. The project will investigate patients with varying levels of cognitive control along with their close partners (sibling or intimate partner) to identify the dynamics of self-regulation and co-regulation in provoked conflict situations in patients with control deficits. To identify the precursors and dynamics of conflict escalation, the project will apply measures of behavioral reactions, skin conductance, simulated or real conflict, fMRI and fMRI-hyperscanning techniques and physiological measures. Neuroimaging data will also be combined with information on stress, control and conflicts in real-life via EMA.

Focus on the investigation of a lack of cognitive control in bullies and victims that contributes to the risk of developing mental health problems. Therefore, the project will assess bullies and their victims in real-life and digital social interactions to investigate how aberrant cognitive and affective prefrontal control and sensitivity to peer rejection with accompanied alterations in autonomic arousal may increase externalizing and internalizing behavior. To this end, a unique combination of ambulatory assessments of (cyber-)bullying, functional neuroimaging (emotion regulation, inhibition, social exclusion), physiological assessments (heart rate variability) and clinical trait-related questionnaires will be applied. Decoding dynamic

Investigate context-dependent aggression triggered by frustrative non-reward or acute social threats. Using newly developed approaches, multiple behavioral domains will be assessed in a semi-naturalistic, autonomous mouse habitat. Specifically, the habitat assesses the inter-individual dynamics of social interactions, aggressions, and hierarchy and the individual reward learning and impulsivity through different integrated modules. Intermittent challenges comprise intruder aggression and frustrative non-rewards. Within this LCD, circuit mechanisms are dissected through chemogenetic interventions, in vivo recordings, and functional MRI in awake mice during task performance. This approach in the first funding period will enable us to disentangle the specific functions of candidate entry points in prefrontal to ventral striatum pathways with respect to their modulation of aggression and dominance for potential interventions.

Address sex-specific NVS (reactive aggression) and CS (different dimensions of psychopathy, proactive aggression) associated risk factors, and risk factor-based biosignatures in young people. Considering the interacting genetic, environmental, and hormonal factors related to these specific aggressive behavior dimensions, C04 will identify specific and shared factors and mechanisms related to NVS and CS in female and male youth with and without pathological aggression. Implementing deep-learning algorithms, sex-specific, data-driven subgroups in relation to dimensions of aggressive behavior will be described and probed against the NVS and CS. Group-level risk factors of aggressive behavior dimensions, and individual risk factor-based subgrouping will be the basis of developing a biologically informed stratification strategy for tailored treatment. Models and classifiers will be established cross-sectionally in available data and replicated in the prospectively collected cross-sectional data (Q01). In addition, C04 will test the models and classifiers for predictive validity in the longitudinal data of the TRR Q01 cohort.

Identify specific neuronal mechanisms related to the NVS and CS in female and male clinical samples with a history of early-life maltreatment (ELM) who exhibit externalizing, aggressive psychopathologies as opposed to internalizing, non-aggressive psychopathologies. We will therefore explore the interaction of the NVS and CS as well as the modulating effects of theory-of-mind (ToM) on the NVS and CS using a series of fMRI and behavioral tasks. Furthermore, we will investigate the role of hormonal stress responses and will use EMA to assess anger and aggression in everyday life. Thus, we will be able to combine behavioral phenotyping in natural conditions of everyday life and neurobiological correlates of psychopathology in order to detect clinically relevant biosignatures for AMD.

The central recruitment platform for collecting and curating a longitudinal dataset for studying individual aggression dynamics related to the neural, cognitive-emotional, neurobiological, psychopathological and environmental factors in patient groups.