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Biological Psychiatry

Projects

A02: Context effects on threat processing in dependence of testosterone levels

Katja Bertsch Sabine Herpertz Ute Habel Isabel Neumann Nick Worm Julius-Maximilians University Würzburg Heidelberg University RWTH Aachen Negative valence system Biological Psychiatry 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.

A04: Implicit chemosensory threat signals as stimulators of amygdala hyperresponsiveness in AMD

Ute Habel Natalia Chechko RWTH Aachen Negative valence system Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

A05: Peripersonal space violations and social threat: daily-life psychological and neural mechanisms of environmental risk for reactive aggression

Heike Tost Andreas Meyer-Lindenberg Central Institute of Mental Health Negative valence system Human Cognitive and Systems Neuroscience Biological Psychiatry
Peripersonal space, the representation of the space immediately surrounding the body, will be studied as an underlying factor for threat experience. Early-life stressors and daily-life stressors will be tested as factors influencing PPS processing and associated specific brain activation patterns. Location tracking and geoinformatics mapping, virtual reality (VR) experiments, physiological stress markers, and brain function during the processing of PPS violations in healthy at- risk individuals will be used to identify predictive biomarkers related to psychiatric risk, enhanced neural behavioral sensitivity to PPS interference and reactive aggression in daily life.

A07: The intestinal microbiota as a regulator of aggressive and impulsive behavior

David Slattery Andreas Reif Goethe University Frankfurt Negative valence system Biological Psychiatry
This translational project investigates sex-dependent behavioral effects of faecal microbiota transplantation to microbiome-depleted mice from AMD patients (selected based on their aggressive and impulsive traits from Q01), as well as healthy controls. Impulsivity will be assessed via the continuous performance test and responses towards acute threat via the escalated resident intruder test. The goal is to determine the sex-dependent effects of faecal transplantation on selected readouts involved in the transfer of the patient’s phenotype to the mice, such as immune parameters, sex hormones, neuronal activity (and morphology, e.g., neurite outgrowth, spines, etc.), and gene expression (e.g., Rbfox1 from prior studies and novel candidates from C01 and C04).

A08: The metabolic lung-brain axis in aggressive behavior in patients with AMD

Thomas Frodl David Slattery Gabriele Ende RWTH Aachen Goethe University Frankfurt Central Institute of Mental Health Negative valence system Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

B01: Neurobehavioral effects of repetitive prefrontal transcranial direct current stimulation (tDCS) on pathological aggression

Carmen Weidler Andreas Reif RWTH Aachen Goethe University Frankfurt Cognitive system Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

B02: Young offenders’ self-regulation deficit as a common mechanism for aggressive behavior and psychopathology - neural mechanisms and role of adverse childhood experiences

Wolfgang Retz Oliver Tüscher Johannes Gutenberg University Mainz Cognitive system Cognitive, Systems and Behavioural Neurobiology Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

B03: A process-based brain-computer interface to modulate aggressive behavior – a real-time fMRI neurofeedback study

Klaus Mathiak Christian Paret Jana Zweerings RWTH Aachen Central Institute of Mental Health Cognitive system Biological Psychiatry
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.

B04: Investigating psychological and neural correlates of intimate partner violence

Lisa Wagels Andreas Meyer-Lindenberg Katja Bertsch Julia Koch Julia Schräder Linda Wilkin-Krug RWTH Aachen Central Institute of Mental Health Julius-Maximilians University Würzburg Cognitive system Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

C01: Gene-environment interactions and the role of impulsivity in responding to acute threats: early life stress and escalated aggression in recombinant inbred mouse strains

Aet O'Leary David Slattery Goethe University Frankfurt Interaction of negative valence system and cognitive system Biological Psychiatry
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

C02: Aggressive decisions in social conflicts: Neuro-cognitive models for healthy individuals and psychiatric patients with high scores of aggression

Christoph Korn Klaus Mathiak RWTH Aachen Heidelberg University Interaction of negative valence system and cognitive system Biological Psychology and Cognitive Neuroscience Cognitive, Systems and Behavioural Neurobiology Human Cognitive and Systems Neuroscience Biological Psychiatry
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.

C03: Distributed network control and interventions to frustrative non-reward and threat triggered aggressions

Wolfgang Kelsch Wolfgang Weber-Fahr Johannes Gutenberg University Mainz Central Institute of Mental Health Interaction of negative valence system and cognitive system Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

C04: The sex-specific role of genes, early adversity, peers, community violence, and puberty related endocrinological changes in adolescent pathological aggression

Christine Margarete Freitag Andreas G Chiocchetti Goethe University Frankfurt Interaction of negative valence system and cognitive system Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

C05: The neuroanatomical underpinnings of clinical aggression and their relationship with the negative valence and cognitive control systems

Christine Ecker Goethe University Frankfurt Interaction of negative valence system and cognitive system Biological Psychiatry
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

C07: Identifying mediators of threat-aggression and experimental manipulation by tDCS

Michael Plichta Wolfgang Retz Goethe University Frankfurt Johannes Gutenberg University Mainz Interaction of negative valence system and cognitive system Biological Psychiatry
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.

Publications

A cognitive neuroscience approach to understanding aggression and its treatment

Ute Habel Lisa Wagels A02: Context effects on threat processing in dependence of testosterone levels A04: Implicit chemosensory threat signals as stimulators of amygdala hyperresponsiveness in AMD B04: Investigating psychological and neural correlates of intimate partner violence Q03: Integrated Research Training Group (RTG) Q04: Central coordination Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry Negative valence system

While anyone can behave aggressively, some people are more prone to aggression than others. We present a neuro-cognitive model and consider several inter-individual differences that confer risk for aggression. Forms of atypical cognitive function include a hyperreactive acute threat response, poor emotion regulation, and mechanisms involved in choosing when to aggress. We show dysfunction in the neural systems mediating these functions may account for aggression in people high in psychopathy/callous unemotional traits, irritability/anger, hostility, impulsivity, and low in frustration tolerance. We then review promising interventions including psychological therapies and pharmaceuticals that might influence the neuro-cognitive underpinnings of these constructs. Although there is no overwhelming “one size fits all” approach to treating aggression, identifying the neural mechanisms implicated in these traits may improve individualized treatments.

Associations of brain structure with psychopathy

Ute Habel Q01: Recruitment and biotyping transdiagnostic risk mechanisms for aggressive behaviors in mental disorders across the life span Biological Psychiatry

Psychopathy is one of the greatest risk factors for serious and persistent violence. In order to detect its neurobiological substrates, we examined 39 male psychopathic subjects and matched controls using structural MR imaging and the Psychopathy Check-List (PCL-R). Individual brain region volumes were calculated using the Julich-Brain and AAL3 atlases. Associations of region volumes with the PCL-R dimensions among psychopathic subjects and differences between both groups were analysed. PCL-R factor 2 assessing lifestyle and antisocial behaviour showed in the psychopathic sample negative associations with volumes of several regions, including pons, nuclei of basal ganglia, thalamus, basal forebrain (CH-4), cerebellar regions and areas in orbitofrontal, dorsolateral-frontal and insular cortices. These findings suggest dysfunctions in specific frontal-subcortical circuits, which are known to be relevant for behavioral control. In contrast, the interpersonal-affective PCL-R factor 1 showed only weak positive and negative associations with orbitofrontal, dorsolateral-frontal and left hippocampal areas (CA1, subiculum), among others, indicating that involved brain regions might be affected to a variable degree in different individuals. The group comparison yielded a significantly reduced total brain volume in psychopathic subjects relative to controls, while pronounced regional focuses of volume differences were found only in the right subiculum, suggesting an interindividually variable pattern of structural deviations in the brains of psychopathic subjects. In conclusion, these findings are compatible with the dimensionality of the PCL-R construct, and suggest a particulary strong association of antisocial behavior to smaller volumes in widespread subcortical-cortical brain regions.