Serotonergic Contributions to Human Brain Aggression Networks

Aggressive behavior is associated with dysfunctional frontolimbic emotion regulation circuits. Recent findings suggest serotonin as a primary transmitter for prefrontal amygdala control. However, the association between serotonin levels, amygdala regulation, and aggression is still a matter of debate. Neurobehavioral models furthermore suggest a possible mediating influence of the monoamine oxidase A gene (MAOA) on this brain-behavior relationship, with carriers of low expressing allele varieties being a risk group for aggression. In the present study, we investigated the influence of brain serotonin modulation and MAOA genotype on functional amygdala connectivity during aggressive behavior. Modulation of serotonergic neurotransmission with acute tryptophan depletion (ATD) and placebo were administered in a double-blind, cross-over design in 38 healthy male participants. Aggressive behavior was modeled in a violent video game during simultaneous assessment of brain activation with functional magnetic resonance imaging (fMRI). Trait aggression was measured with the Buss-Perry Aggression Questionnaire (BP-AQ), and MAOA genotypes were assessed from blood samples. Voxel-wise functional connectivity with anatomically defined amygdala was calculated from the functional data. Tryptophan depletion with ATD reduced aggression-specific amygdala connectivity with bilateral supramarginal gyrus. Moreover, ATD impact was associated with trait aggression and MAOA genotype in prefrontal cortex regions. In summary, serotonergic corticolimbic projections contribute to aggressive behavior. Genotype-specific vulnerability of frontolimbic projections may underlie the elevated risk in low expressing allele carriers

Étude neuroanatomique fonctionnelle de l'émoussement affectif dans la schizophrénie : les implications du traitement à la quetiapine

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

The evolutionary old forebrain as site of action to develop new psychotropic drugs

Background: Previously, the authors have developed a model of how reward-seeking and distress- avoiding behaviour is regulated by the human brain. The forebrain's evolution in vertebrates was taken as a starting point. Aims: The authors want to inspire colleagues to study in particular the pharmacological effects on the described ancient forebrain structures in order to modify specific symptoms of mental disorders. Methods: Compilation of data and ideas of previous articles, with examples to illustrate. Results: A primary (lamprey-like), secondary (frog-like) and tertiary (mammal-like) forebrain can be distinguished, organized according to a Russian doll model. The first constituent is primarily involved in producing the emotional response, while the last is principally concerned with constructing conscious cognitive behaviour (including verbal and written communication). Mental disorders comprise (partly related and partly unrelated) biological and rational phenomena. The secondary system regulates the intensity of reward-seeking and distress-avoiding behaviour. An essential component of the primary forebrain evaluates the results of behavioural actions: the lateral habenula-projecting pallidum. These neurons regulate the activity of ascending dopaminergic pathways. The authors suggest that these habenula-projecting pallidum neurons are targeted by subanaesthetic dosages of ketamine. The medial habenula is enriched with nicotinergic acetylcholine receptors and regulates the activity of ascending adrenergic and serotonergic neurons. This may link varenicline-induced hostility to selective serotonin reuptake inhibitor-induced aggression. Conclusions: Studying the effects of new compounds on the primary and secondary brains in lampreys and frogs may yield interesting new treatments of mental disorders

Clinical correlates of emotional dysregulation in bipolar disorder spectrum: a case-control study

openL'attuale studio si propone di studiare e quantificare le differenze tra i pazienti con BD, quelli con BPD, e controlli sani in (a) disregolazione emotiva utilizzando Difficoltà nelle scale di disregolazione delle emozioni (DERS), (b) impulsività valutata da Barratt Inibiion Scale (BIS-11), (c) abusi della prima infanzia utilizzando il Child Trauma Questionnaire (CTQ) e (d) funzionamento quotidiano con il World Health Organization Disability Assessment Schedule (WHODAS.2). Questo studio si propone di aiutare i medici nel compito impegnativo di distinguere tra i pazienti con BD e BPD, contribuendo così al perfezionamento della diagnosi precoce di questi disturbi.The current study aims to investigate and quantify differences between patients with BD, those with BPD, and healthy controls in (a) emotional dysregulation using Difficulties in emotion dysregulation scales (DERS), (b) impulsivity assessed by Barratt Inhibition Scale (BIS-11), (c) early childhood abuses using the Child Trauma Questionnaire (CTQ) and (d) daily functioning with the World Health Organization Disability Assessment Schedule (WHODAS.2). This study aims to assist clinicians in the challenging task of distinguishing between patients with BD and BPD, thereby contributing to the refinement of the earlier diagnosis of these disorders

Neural changes following a body-oriented resilience therapy with elements of kickboxing for individuals with a psychotic disorder:a randomized controlled trial

Individuals with a psychotic disorder are at an increased risk of becoming the victim of a crime. A body-oriented resilience therapy (BEATVIC) aimed at preventing victimization by addressing putatively underlying factors was developed. One of these factors is social cognition, particularly facial affect processing. The current study investigated neural effects of BEATVIC on facial affect processing using two face processing tasks. Participants were randomized to either BEATVIC or a 'Befriending' control group. Twenty-seven patients completed an Emotional Faces task and the Wall of Faces task during fMRI, pre- and post-intervention. General linear model analyses yielded no differences between groups over time. Independent component analyses revealed increased activation of the salience network to angry and fearful faces in BEATVIC compared to Befriending. Increased activation of the salience network may suggest an increased alertness for potentially dangerous faces

Neurobiological mechanisms of control in alcohol use disorder – Moving towards mechanism-based non-invasive brain stimulation treatments

Alcohol use disorder (AUD) is characterized by excessive habitual drinking and loss of control over alcohol intake despite negative consequences. Both of these aspects foster uncontrolled drinking and high relapse rates in AUD patients. Yet, common interventions mostly focus on the phenomenological level, and prioritize the reduction of craving and withdrawal symptoms. Our review provides a mechanistic understanding of AUD and suggests alternative therapeutic approaches targeting the mechanisms underlying dysfunctional alcohol-related behaviours. Specifically, we explain how repeated drinking fosters the development of rigid drinking habits and is associated with diminished cognitive control. These behavioural and cognitive effects are then functionally related to the neurobiochemical effects of alcohol abuse. We further explain how alterations in fronto-striatal network activity may constitute the neurobiological correlates of these alcohol-related dysfunctions. Finally, we discuss limitations in current pharmacological AUD therapies and suggest non-invasive brain stimulation (like TMS and tDCS interventions) as a potential addition/alternative for modulating the activation of both cortical and subcortical areas to help re-establish the functional balance between controlled and automatic behaviour

Molecular modelling of interactions between antipsychotic drugs and receptors mediating antipsychotic effects and important side effects

Dopamine and serotonin are two neurotransmitters that exert their actions through mediation of dopaminergic and serotonergic receptors respectively. The receptors in focus in the current study, are the dopamine D2 and serotonin 5-HT2A receptors. Common for both receptors is that they are class A G-protein-coupled receptors consisting of seven transmembrane helices embedded in the lipid membrane of neurons. Imbalance and disruption of especially the dopamine system in the CNS may result in hallucinations, delusions, and lowered levels of motivation, which are treated with antipsychotic drugs that predominantly antagonize dopamine D2 and serotonin 5-HT2A receptors. The main aim of this thesis is to get a deeper understanding of the mechanisms of action and side effects of antipsychotics utilizing induced fit docking and molecular dynamic simulations. Our results suggest that there is a correlation between the binding affinities of the antipsychotic drugs to different aminergic receptors, and the most common side effect observed. Additionally, MD simulations revealed that antipsychotic drugs with different intrinsic activity, bind to the dopamine D2 receptor in distinct ways

Depressive and psychotic symptoms in schizophrenia:Focus on networks and treatment

This thesis has two main aims. First, to review and increase knowledge concerning symptom interaction in patients with schizophrenia, with a specific focus on co-occurring depressive symptoms and its neural correlates in major depressive disorder (Part I and II). Second, to review and investigate different treatment aspects and outcomes in schizophrenia (quality of life, depressive symptoms and mortality) (Part III). In sum, both network studies showed the importance of depressive symptoms in the symptom networks of patients with schizophrenia and showed the stability of such a network structure. Although the network approaches has several issues of debate, it is a promising new way of thinking about psychopathology. The network approach is an example of a new conceptualisation of psychopathology as dynamic systems that change over time. Additionally, this view on mental illness facilitates a more transdiagnostic approach, in which emotion regulation should be an important target for future studies. Given the frequent co-occurrence of depressive symptoms in patients with schizophrenia, its centrality, its correlations with suicidality and influence on quality of life, it is highly important to adequately treat co-occurring depressive symptoms and episodes. Systematically following the provided treatment guide to treat depressive symptoms or episodes might be useful. Additionally, meta-analyses showed that schizophrenia patients who do not use antipsychotics have a higher mortality risk compared to patients that use antipsychotics. In a similar way, continuous use of clozapine was related to a lower mortality risk compared to patients using other antipsychotics

Life on a scale:Deep brain stimulation in anorexia nervosa

Anorexia nervosa (AN) is a severe psychiatric disorder marked by low body weight, body image abnormalities, and anxiety and shows elevated rates of morbidity, comorbidity and mortality. Given the limited availability of evidence-based treatments, there is an urgent need to investigate new therapeutic options that are informed by the disorder’s underlying neurobiological mechanisms. This thesis represents the first study in the Netherlands and one of a limited number globally to evaluate the efficacy, safety, and tolerability of deep brain stimulation (DBS) in the treatment of AN. DBS has the advantage of being both reversible and adjustable. Beyond assessing the primary impact of DBS on body weight, psychological parameters, and quality of life, this research is novel in its comprehensive approach. We integrated evaluations of efficacy with critical examinations of the functional impact of DBS in AN, including fMRI, electroencephalography EEG, as well as endocrinological and metabolic assessments. Furthermore, this work situates AN within a broader theoretical framework, specifically focusing on its manifestation as a form of self-destructive behavior. Finally, we reflect on the practical, ethical and philosophical aspects of conducting an experimental, invasive procedure in a vulnerable patient group. This thesis deepens our understanding of the neurobiological underpinnings of AN and paves the way for future research and potential clinical applications of DBS in the management of severe and enduring AN