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Negative valence system

The negative valence system is primarily responsible for reactions to aversive situations and includes the constructs of acute threat, potential threat, sustained threat, as well as loss and frustrative non-reward. The acute threat system is related to the defensive motivational system, which protects the organism from a perceived danger initiating adaptive responses. The frustrative non-reward system is triggered by the withdrawal or prevention of expected rewards, which may lead to an arousal exceeding normal regulatory capacity and thus precipitating aggressive or antisocial responses.

We hypothesize that a perceived or potential danger can trigger a fight response in individuals hypersensitive to threat. Similarly, aggressive behavior may be a response to frustration. Anger in response to frustrative non-reward can promote aggressive behaviors. Investigations of this topic will address whether the aggressive response is determined by increased and altered bottom-up signaling of threat cues and/or frustrative non-reward, and how this is reflected on the neural, neurochemical, and hormonal levels. The focus is on the identification of specific negative valence system dysfunctions relevant to aggression in mental disorders.

Projects

A01: The neural code of stimulus-triggered territorial aggression

Marc Spehr Lena Terlau RWTH Aachen Negative valence system Molecular Biology and Physiology of Neurons and Glial Cells
A unique experimental model will be used to study the neurobiological basis of aggressive animal behavior and translate novel findings about its cellular and circuit underpinnings into human phenotypes of pathological aggression. Specifically, the post-weaning social isolation model of early-life adverse experience allows experimental access to dissect the ‘switch’ from functional adaptive aggression to excessive pathological aggressive behavior. In male mice, conspecific chemostimuli trigger innate aggressive behavior. The relevant aggression-promoting circuits along the(sensory) input to (aggressive) output axis comprise the accessory olfactory bulb (AOB), a hub for processing of social chemosignals, and the medial amygdala (MeA), a crucial control centre for regulation of aggressive behavior. Therefore, this project addresses the principles that govern aggression-promoting information transfer along the AOB-to-MeA signaling pathway.

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.

A03: Modulation of aggression by acute threat

Gabriele Ende Christian Schmahl Central Institute of Mental Health Negative valence system Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

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.

A06: Decoding dynamic reciprocal neural mechanism underlying reactive aggression: Insights from fMRI and fNIRS hyperscanning

Kerstin Konrad Andreas Meyer-Lindenberg Vanessa Reindl RWTH Aachen Central Institute of Mental Health Negative valence system Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry
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.

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.

Publications

Gender differences in aggression associated with mental disorders

Katja Bertsch Ute Habel A02: Context effects on threat processing in dependence of testosterone levels Biological Psychiatry Clinical Psychiatry, Psychotherapy, Child and Adolescent Psychiatry Negative valence system

Aggressive behavior shows striking gender differences. Cross-cultural research shows that men are more likely to engage in physical aggression, while women tend to use indirect forms of aggressive behavior. Aggression is a multifactorial phenomenon influenced by situational, genetic, psychological and other factors. Despite being a transdiagnostic feature in numerous mental disorders, gender-specific differences and the underlying influencing factors have not yet been sufficiently investigated. Many findings originate from older publications and methodologically sound and in particular behavior-based investigations are rare. This article provides a narrative literature review that summarizes the current state of research on gender differences in aggression in selected mental disorders, including substance use disorders, psychotic disorders and borderline personality disorder. The implications for future research and the clinical practice are discussed.

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.

Voice as objective biomarker of stress: association of speech features and cortisol

Michael Plichta Andreas Reif C07: Identifying mediators of threat-aggression and experimental manipulation by tDCS Negative valence system

Objective:: Cortisol is a well-established biomarker of stress, assessed through salivary or blood samples, which are intrusive and time-consuming. Speech, influenced by physiological stress responses, offers a promising non-invasive, real-time alternative for stress detection. This study examined relationships between speech features, state anger, and salivary cortisol using a validated stress-induction paradigm.