Biologische Psychiatrie

Der Fokus liegt auf den Einflüssen eines provozierenden Kontexts auf die soziale Bedrohungsverarbeitung bei AMD unter unterschiedlichen Testosteronspiegeln. Insbesondere zielt das Projekt darauf ab, die modulierende Funktion von Kontext unter Testosteronanwendung versus -suppression auf Bedrohungssensitivität bei gesunden Kontrollpersonen sowie Patientengruppen zu analysieren. Zusätzlich werden wir den Einfluss endogener Hormonvariationen (Testosteron, Oxytocin, Östrogen und Cortisol) auf NVS bei hoch- versus niedrig-aggressiven Patienten in einer großen Patientengruppe untersuchen, die in Q01 rekrutiert wird. Mit dieser Stichprobe werden wir versuchen, multidimensionale Biosignaturen basierend auf Hormonspiegeln in Kombination mit fMRT-Messungen von Amygdala und Amygdala-präfrontaler Konnektivität, NVS-Messungen durch Fragebögen, Aggressionsmessungen und psychopathologischen Daten zu identifizieren.

Wir nutzen bedrohungsbezogene chemosensorische Stimuli, nämlich Körpergeruch, der während aggressivem Verhalten (Boxen) erworben und unbewusst wahrgenommen wird, um erhöhte Amygdala-Reaktionen auf Bedrohungsreize bei aggressiven Patienten zu untersuchen. Körpergerüche haben den großen Vorteil, direkt in die Amygdala projiziert zu werden und dabei kortikale Vorverarbeitung zu umgehen, wodurch die Differenzierung von Mechanismen zwischen bottom-up veränderter limbischer Verarbeitung und top-down modulierter veränderter kognitiver Bewertung ermöglicht wird. Wir untersuchen das Potenzial solcher Körpergerüche, Reaktionen auf ambigue visuelle soziale Hinweise in Richtung Bedrohung zu verzerren, sowie ihre Effekte während Verletzungen des peripersonalen Raums (PPS), wo sie besonders relevant sein könnten.

Der peripersonale Raum, die Repräsentation des Raums unmittelbar um den Körper herum, wird als zugrunde liegender Faktor für Bedrohungserleben untersucht. Frühe Lebensstressoren und Alltagsstressoren werden als Faktoren getestet, die PPS-Verarbeitung und assoziierte spezifische Hirnaktivierungsmuster beeinflussen. Standortverfolgung und geoinformatisches Mapping, Virtual-Reality (VR)-Experimente, physiologische Stressmarker und Hirnfunktion während der Verarbeitung von PPS-Verletzungen bei gesunden Risikopersonen werden verwendet, um prädiktive Biomarker zu identifizieren, die mit psychiatrischem Risiko, erhöhter neuraler Verhaltenssensitivität gegenüber PPS-Störungen und reaktiver Aggression im Alltag zusammenhängen.

Dieses translationale Projekt untersucht geschlechtsabhängige Verhaltenseffekte der fäkalen Mikrobiota-Transplantation von AMD-Patienten (ausgewählt basierend auf ihren aggressiven und impulsiven Merkmalen aus Q01) sowie gesunden Kontrollpersonen an mikrobiomdepletierte Mäuse. Impulsivität wird über den Continuous Performance Test und Reaktionen auf akute Bedrohung über den Escalated Resident Intruder Test erfasst. Das Ziel ist, die geschlechtsabhängigen Effekte der fäkalen Transplantation auf ausgewählte Parameter zu bestimmen, die am Transfer des Patientenphänotyps auf die Mäuse beteiligt sind, wie Immunparameter, Sexualhormone, neuronale Aktivität (und Morphologie, z.B. Neuritenwachstum, Spines usw.) und Genexpression (z.B. Rbfox1 aus früheren Studien und neue Kandidaten aus C01 und C04).

Beta-Hydroxy-Butyrat (BHB), ein Ketonkörper, ist negativ mit aggressivem Verhalten assoziiert. BHB ist ein Metabolit und ein aktives Signalsubstrat, das an der epigenetischen Regulation von z.B. neurotrophen Faktorgenen im Gehirn beteiligt ist. Von den drei Hauptketonkörpern Aceton, Acetoacetat und BHB ist Aceton eine sehr flüchtige Verbindung, die hauptsächlich über die Atmung ausgeschieden wird und daher nicht-invasiv in der Atemluft gemessen werden kann. Eine Reduktion von Aceton in der Atemluft korreliert nachweislich stark mit BHB im Blut und ist mit dem Schweregrad der Symptome bei Schizophrenie assoziiert (Jiang et al. 2022). Mittels MR-Spektroskopie zielt A08 darauf ab, (1) festzustellen, ob Aceton und andere flüchtige organische Verbindungen in der Atemluft mit Aggression und akuter Bedrohungsverarbeitung bei psychischen Erkrankungen assoziiert sind, (2) zu untersuchen, ob diese Atemmarker mit direkten metabolischen Hirnkorrelaten (wie BHB, Glutamat) und mit dem brain-derived neurotrophic factor (BDNF)-Spiegel im Plasma assoziiert sind. In einem translationalen Ansatz werden wir (3) testen, ob die Supplementierung von BHB aggressives Verhalten bei Mäusen reduziert.

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.

Probe the self-regulation of CS networks in adults and adolescents diagnosed with mental disorders related to frequent stress-associated affective outbursts and aggressive symptoms in posttraumatic stress disorder (PTSD), and BPD. The patients will subsequently be trained to regulate the frontal control network to varying acute threat in a double-blind, randomized, controlled design. An immersive, virtual brain- computer-interface (BCI) will allow for a culture- and age-sensitive, personalized training approach. The aim of the present investigation is to assess feasibility of the approach according to four clinical markers: Reduction of perceived threat and aggressive behavior in daily life, improved control in the face of unfair provocation, and neurofeedback-specific modulation of the neural networks.

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.

Sex-dependent effects and gene-environment interactions will be investigated by applying escalating aggression paradigms. Specifically, the project will investigate the effects of early life stress on aggression in response to threat and hyperactivity as well as social decision-making in 32 BXD mouse strains, the progenitor strains (C057Bl/6J and DBA/2J), and the F1 BXD cross. The project aims to identify the quantitative trait loci (QTL) and putative candidate genes contained within the QTL and associate them with specific behavioral responses of stressed and unstressed cohorts of mice. The publicly available database GeneNetwork (www.genenetwork.org) will be used to validate the findings which include measurements of mRNA and protein expression, and methylation patterns in mouse brains

Develop virtual scenarios to assess decision strategies in cartoon-like and naturalistic contexts. The core question is how healthy individuals and patients make (mal-)adaptive aggressive decisions in social conflicts given their threat sensitivity, cognitive functions, and learning experience. We plan to present mathematically well-defined aggressive decision scenarios to healthy participants as well as patients across diagnostic categories with high scores of aggressive behavior, threat sensitivity, and inference of hostile intent in others. Computational models that accurately explain behavioral choices and neural responses (tested using fMRI and pupillometry) will be developed to identify the aggressive decision strategies humans employ in approach-avoidance conflicts of increasing complexity and ecological realism. The purpose will be to determine if patients use overly aggressive strategies that are not warranted by the necessary defense of self-threats and underlying neural circuits.

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.

Link questionnaire measures of aggression to specific neural substrates using structural MRI. The resulting patterns of aggression-related neuroanatomical variability will be co- registered with the Allen Human Brain Atlas providing gene-expression data, to highlight genes with a spatial pattern of expression that matches the neuroimaging findings. Utilizing the neurotypical control data, a normative model of neuroanatomical diversity within the NVS and CS will be established to quantify neuroanatomical abnormalities within these systems in individual cases

Test the interaction of the CS and frustrative non-reward as part of the NVS. It will investigate the electrophysiological correlates of frustrative feedback in aggression-prone patients. In the aftermath of induced stress, an EEG task-battery including frustrative feedback will be applied for extraction of error-related negativity (ERN) and contingent negative variation to monitor electro-physiologic signaling of the relevant learning and frustration processes. In half of the participants, tDCS over the prefrontal cortex will be applied to enhance cognitive control, with participants being put into a stress context inducing frustration.

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.