Brain in Trouble - Introduction to Mental Health PDF

Brain in trouble Inhoudsopgave {#inhoudsopgave.Kopvaninhoudsopgave} ============= [Week 1: Addiction, Impulsivity & ADHD 2](#week-1-addiction-impulsivity-adhd) [Introduction to Brain in Trouble 2](#introduction-to-brain-in-trouble) [Etiology of mental traits and conditions 3](#etiology-of-mental...

Brain in trouble Inhoudsopgave {#inhoudsopgave.Kopvaninhoudsopgave} ============= [Week 1: Addiction, Impulsivity & ADHD 2](#week-1-addiction-impulsivity-adhd) [Introduction to Brain in Trouble 2](#introduction-to-brain-in-trouble) [Etiology of mental traits and conditions 3](#etiology-of-mental-traits-and-conditions) [Impulsivity 13](#impulsivity) [Addiction is a brain disease I 20](#addiction-is-a-brain-disease-i) [Addiction is a brain disease II 28](#addiction-is-a-brain-disease-ii) [ADHD 33](#adhd) [Neurodiversity for ASD & ADHD 41](#neurodiversity-for-asd-adhd) [Week 2: Cognitive enhancers, deep brain stimulation & eating disorders 43](#week-2-cognitive-enhancers-deep-brain-stimulation-eating-disorders) [Introduction to (ab)normal behavior 43](#introduction-to-abnormal-behavior) [Obesity -- body weight regulation, pathophysiology and treatment 44](#obesity-body-weight-regulation-pathophysiology-and-treatment) [DBS in psychiatry 60](#dbs-in-psychiatry) [Healthy brain -- part 1 -- introduction 66](#healthy-brain-part-1-introduction) [Healthy brain -- part 2 -- Increasing Peak Performance 74](#healthy-brain-part-2-increasing-peak-performance) [Healthy brain -- part 3 -- increasing well-being 76](#healthy-brain-part-3-increasing-well-being) [Healthy brain -- part 4 -- gratitude letter 79](#healthy-brain-part-4-gratitude-letter) [Healthy brain -- part 5 -- increasing well-being 80](#healthy-brain-part-5-increasing-well-being) [Cognitive enhancers 84](#cognitive-enhancers) [Week 3: Mood & social behaviour 91](#week-3-mood-social-behaviour) [Depression -- part 1 91](#depression-part-1) [Depression -- part 2 102](#depression-part-2) [The bright side of mental illness -- resilience 105](#the-bright-side-of-mental-illness-resilience) [Neurobiology of morality and antisocial behaviour I 112](#neurobiology-of-morality-and-antisocial-behaviour-i) [Part 1 -- ASPD vs psychopathy 112](#part-1-aspd-vs-psychopathy) [Part 2 -- neuroimaging studies 113](#part-2-neuroimaging-studies) [Part 3 -- empathy in psychopaths 115](#part-3-empathy-in-psychopaths) [Part 4 -- neurodevelopmental basis of antisocial behavior 117](#part-4-neurodevelopmental-basis-of-antisocial-behavior) [Part 5 -- Environmental and genetic factors 120](#part-5-environmental-and-genetic-factors) [Part 6 -- are psychopathic tendencies always a bad thing? 122](#part-6-are-psychopathic-tendencies-always-a-bad-thing) [Real-life neuroscience 124](#real-life-neuroscience) Week 1: Addiction, Impulsivity & ADHD ===================================== Introduction to Brain in Trouble -------------------------------- **ADHD** - Lifetime-prevalence of ADHD is 3-5% in adults and 4-8% in children. Lifetime- prevalence = it occurs at some time in your life. **Eating Disorders Statistics** -\ Lifetime-prevalence of anorexia nervosa, boulimia nervosa, binge-\ eating disorder and other eating disorders varies from less than 0.5%\ up to 2,5%.\ Almost 50% of people with eating disorders meet the criteria for\ depression.\ Only 1 in 10 men and women with eating disorders receive\ treatment.\ Eating disorders have a high mortality rate **Deep brain stimulation in Psychiatry --** OCD, Depression. Depression is a major cause of morbidity worldwide\ Lifetime prevalence varies widely, from 3% in Japan to 17% in the US.\ In most countries the number of people who would suffer from depression during their lives falls within an 8--12% range. Etiology of mental traits and conditions ---------------------------------------- Trait or disorder? - Impulsivity, mood, (anti) social behaviour, stress-sensitivity, resilience and vulnerability are behavioural traits - Each trait exists along a spectrum - Impulsivity (extremely thoughtful, difficulties decision taking -- extremely impulsive) - Border between normal and abnormal behaviour? (What is normal? What is abnormal? Who decides this?) - A variation or a disorder? - Other traits: IQ, extraversion, blood pressure... - Disorders: diabetes, obesitas, autism (?), depression, schizophrenia HOW do traits and disorders arise in general? Which factors can contribute to traits / (mental) characteristics and brain disorders -- genes, environmental factors (stress, alcohol, family, pregnancy, food). Nature -- Nurture discussion - Past: tendency to explain disease via 'nurture' concept - Autism = 'refrigerator mother' (cold) -- having a cold and distant mother - Homosexual orientation = overly present mother - Later: role biological factors clearer ('nature') **Etiology** *Etiology is the study of the causes, origins, or reasons behind the way that things are, or the way they function, or it can refer to the causes themselves. -\> Wikipedia* Classical nature -- nurture discussion: - Hard reductionism: 'all psychiatric illness is best explained solely in terms of molecular neuroscience'. But etiological models for psychiatric disease need to be pluralistic or multilevel in order to explain mental traits and psychiatric illness. Best understood from biological, psychological and sociocultural, economic perspectives. Break down dichotomy between nature-nurture, but view brain as in constant interaction with environment, society and culture via plasticity. Some traits have a more nurture load and some more nature, but there is a constant connection, and they are shaping traits. Most brain disorders are complex (several factors to shape), multifactorial disorders. Both genetic and environmental factors involved in etiology. Often: complex interactions and causal loops. Not one cause. [Genes ] From twin + adoption studies; several behavioral traits and psychiatric diseases moderate / high heritability. *Heritability* = proportion of variance in symptoms that is explained by the variance in genetic factors. So, 75% heritability does not mean that you have 75% probability that you have it. It is a variable at population level, not individual level. The variation you see in their symptoms can be explained by the variation among these people. Major depression: 40-50%. ADHD: 75%. Autism, bipolar disorder, schizophrenia around 80%. 'Human genome project' -- Expectation: easy to find risk genes. Contrary: very difficult. 'Missing heritability' = The missing heritability problem arises from the difference between heritability estimates from genetic data and heritability estimates from twin and family data across many physical and mental traits. But: we KNOW genes play a substantial role. Model of single / few risk genes = overly simplistic paradigm. [Genes and Psychiatry] Classical theory = single genes cause mental illness. Single abnormal gene \> abnormal gene product \> neuronal malfunction \> mental illness. Single abnormal gene is not sufficient to cause mental disorders. What is pathway from gene to mental illness? New explanations, new hypotheses, new models for pathway 'genotype to phenotype' - 1\. 'Complex Genetics' or 'Diathesis-Risk Model' (explained in lecture Etiology) - 2\. 'Differential Susceptibly to Environment Hypothesis' (explained in lecture 'Neurobiology of Resilience') - 3\. 'Balancing Selection Hypothesis' (explained in course Molecular Principles of Brain Disorders, minor Neuroscience) New hypotheses and new models are complex.\ New ways of doing research and 'unravel' these pathways from 'genotype to phenotype' -\> 'endophenotype approach' -\> (in between) means endophenotype. Stress -- diathesis model' (diathesis = risk). Stress increases your risk. Predisposition (genetic) + environmental stress \> disease. New paradigm: - Hypothesis: mental illness is caused by multiple small contributions from several genes, all interacting with environmental stressors \> 'Complex genetics'. - Complex set of risk factors that *bias* person toward illness but do not *cause* it (inherits risk not disease). - Reaching tipping point: high probability of developing disorder (threshold). - Concept also applies to hypertension, obesitas, diabetes. [Endophenotype approach] Path from gene \> mental illness. New ways of doing research and 'unravel these pathways from 'genotype to phenotype' \> endophenotype approach. Pathway 'genotype to phenotype' is much more complex! Solution: important *intermediaries* between gene (genotype) and disease/behaviour (phenotype). Create an extra set of variables to make the pathway easier to unravel -\> endophenotype approach. Endophenotypes are variables that are somewhere in between genotype and phenotype: measurable, inheritable and closely linked to disease. More precisely measurable than illness itself.\ There are two types: - Biological endophenotypes - Symptom/system endophenotypes *Biological endophenotypes* Measurable biological phenomena: - Electrophysiological response to startle (neurobiological response in EEG but is different in people with schizophrenia -- abnormal response to startle is associated with schizophrenia) - Neuroimaging response to information processing - Activation of certain brain circuit (activation of amygdala are above normal in anxiety and depression) *Symptom/system endophenotype* Single symptoms associated with mental illness: - Insomnia - Executive dysfunction (problems with planning or prioritizing) - Hallucinations - Poor fear conditioning - Anhedonia (problem with experiencing pleasure) - Extra set of variables that try to explain the pathway from DNA to behaviour. Gene \> molecules \> circuits \> information processing (biological phenotype) \> single symptom (system endophenotype) \> full syndrome of mental disorder. Closer to the gene on pathway \> more readily linked to gene: Link gene to endophenotype is easier than to disease. Genes only loosely linked to psychiatric disorders, therefore hard to identify. [Psychopathology and brain circuits] Etiology of psychiatric disorders is moving beyond single receptors, enzymes and other molecules as causes for mental illness. We used to say that depression is caused by lack of serotonin, because by accident we discovered medications that had an impact, so we thought it plays a major role. But that is far to simplistic, because it is a combination of many things. New paradigm: psychiatric symptoms are increasingly linked to malfunctioning in specific brain circuits. Genes + environmental risk factors conspire to produce inefficient information processing in neuronal circuity. Genes create proteins which are your building blocks for neural circuit, so if there is something wrong with your genes, you may have problems in your neural circuit. Brain imaging focuses on brain circuits. Why are subtle molecular abnormalities not more 'penetrant' (visible) at behavioural level? Why does a single abnormal gene which causes an abnormal protein not directly to translate into problems at behavioural level?\ We have a backup system. Multiple genes are coding for multiple proteins, creating multiple brain circuits that offer a redundancy to the organism. Redundancy creates the backup system.\ Risk genes are not *necessarily sufficient* to cause mental illness. Combination with environmental risk factors (stress, life events, biological stressors such as viruses, toxins..). [Social-ecological framework:] Afbeelding met tekst, cirkel, schermopname, Lettertype Automatisch gegenereerde beschrijving 'Social-ecological framework': no single factor can explain. Dynamic interplay of multiple risk and protective factors. Risk and protective factors: occurring along 'social ecology continuum': - Individual - Relationship - Cultural/environmental factors \*Also, genetic factors are individual factors! *Environmental factors* Pre/peri natal risk factors: - Maternal stress during pregnancy - Maternal nutritional deficiency - Maternal use of tobacco / alcohol /drugs / medications - Birth complications - Perinatal nutritional deficiency - Maternal separation Social factors: - Abuse: sexual, physical, emotional, neglect - Poor parental care Biological environmental factors: - Infections, toxins, brain traumas, drug use - Stressful life events Social: - Low SES, poverty, community violence - (Mental) health care & health care policy: access to care, stigmatization of mental health problems. - Minority group position, cultural factors, religious factors How can environmental factors exert their influence? Altered gene expression via: - Stress system - Epigenetics [Stress system: ]  Untitled.png HPA-axis: Stress \> hormone cortisol. Cortisol is important in the defense response: protective + promote adaptation. Cortisol binds to glucocorticoid receptor (GR) in body. GR acts as transcription factor and can alter the gene expression. GR also in several brain areas. GR in hypothalamus, hypophysis and hippocampus: negative feedback loop \> shuts down CRF release. Sustained high levels of cortisol \> harmful \> hypertension, immunosuppression, cardiovascular disease, structural effects hippocampus + amygdala, increased chance psychopathology. Early life stress \> lifelong overactive HPA-axis (less GR = less negative feedback to shut system down). Hope: evidence that prenatal stress can be moderated by quality of post-natal care. - Can alter the gene expression. Stress-system consists of two pathways -- fast and slow. Fast-acting pathway is nothing more than the sympathetic part of the autonomic nervous system. Fast reaction uses neurotransmitter noradrenaline and affects several organs in the body. Quick response but it doesn't last long. Slow-acting pathway is part of the bigger hormonal system of your body. Hormones are molecules that have a slower response, but a long-lasting response compared to neurotransmitters. The endocrine or hormonal system has a more long-lasting effect. Hormonal system works by having a master gland -- the pituitary gland. Is under control of the hypothalamus and together they control all the bodily glands and control many different pathways. We only look at the stress-pathway or HPA-axis. H -- hypothalamus, P - pituitary gland, A -- adrenals (releases neurotransmitters and hormones). Detect stress? Hypothalamus release corticotrophin releasing factor (CRF) onto pituitary gland. CRF binds to CRF receptors, and these receptors will tell the pituitary gland to synthesize and release adrenocorticotrophic hormone (ACTH). ACTH will be released into the bloodstream and effect the adrenals. Tell the adrenals to release molecule called glucocorticoid hormones of which cortisol is the most important one. Cortisol is main stress hormone in our system, bind to all body cells, because all body cells contain receptors of cortisol. When cortisol binds to its receptor, the complex will act as a transcription factor. Transcription factor is a molecule that affects gene expression by binding to the first part of a gene on the DNA, promoter. It will change gene expression and protein expression and the amount of proteins of building blocks that your body will make in response to stress. This is to adapt to the stress -\> adaptive stress response. Stress via cortisol also inhibits your immune system, because that system uses a lot of energy, and your body needs to choose when in huge stress. To long cortisol can be dangerous and has negative effects: vulnerable for infections (shut-down immune system), cardiovascular system, toxic for the brain. How does your body shut-down this system? Normally cortisol will shut itself down. Glucocorticoid, which cortisol is most important, will make sure they shut down their own production. Cortisol also binds to specific brain cortisol receptors and is another type than in bodily cells. When cortisol comes from the adrenals and goes into the whole body it will bind to brain cortisol receptors at the level of pituitary gland, hypothalamus and even hippocampus. Binding will shut down the CRH. And binding of cortisol at pituitary gland will shut down production of ACTH and hence it will shut down production and release of cortisol. We call this *negative-feedback loop.* Healthy stress system is a system with plenty brain cortisol receptors. [Epigenetics] Life experiences \> literally change person's mind.\ Genetic means DNA and DNA is the molecule that contains all the information, the blueprints, to make your protein, building blocks of an organism.\ DNA -\> RNA -\> mRNA -\> protein -\> we can mess with this process by chemically coding DNA -\> epigenetics.\ Chemically coating the DNA. Ease or block access to the genes on DNA. Coating alters gene expression, but NOT genetic code! 'Environmental programming' of gene expression -- epigenetic changes.  Transcription factors bind to the beginning part of a gene, the non-coding part, which we call the promoter. Enzymes bind and create a copy where they use DNA as a template. Untitled 2.png Epigenetics interfere with this process by sticking sticks out of the DNA. These sticks are methyl groups, methylation is one of the chemical modifications that can happen in the body and that we will refer to as epigenetic modifications. Chemical switches that turn genes either on or off and thereby alter gene expression. Chemical changes alter gene expression by influencing the amount of methylation-\> high methylation decreases gene expression because the transcription factor cannot bind and so the gene cannot be enfolded. In 2004 breakthrough in neurosciences and psychology. Since 1997 known that variations in maternal care affect HPA-axis responses to stress in offspring. Mechanisms unknown. Parenting practices can profoundly shape child's development and mental health \> evidence via epigenetics!  Epigenetic programming by maternal behavior in rats. Mothers lick and groom their offspring; this equals good maternal care in the rat world. Set in motion cascade of events that will in the result in offsprings with low anxiety and a normal stress system. High levels of serotonin will make it possible that a certain transcription factor will bind to the promoter of a gene for cortisol receptors in a rat -\> important for shutdown of stress system. Maternal care: Increased expression of glucocorticoid receptors in the hippocampus -\> able to shut down stress system. The youngsters of a caring mother had lower corticosterone levels and were less anxious. The youngsters of a more avoidant/less caring mother were more anxious and had high corticosterone levels. Molecular neuroscientific basis of parental care early in life! Link between psychological / societal level (binding, affective care, maternal care) and molecular neuroscience and back (general mental wellbeing, psychopathology). REMINDER: psychopathology is NOT psychopathy. Parental care influences the activity of the neural systems that regulate stress reactivity and cognition in offspring through the epigenetic regulation of gene expression. Broader social and economic context can influence the quality of parental care. Negative effects of poor parental care can be reversed by good quality care by others. [Gene-environment interactions] Gene-environment interaction between MAO-A gene and childhood maltreatment on outcome ASPD. Short allele of 5HTT increases chance in depression when life stress is present. Effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotrophin releasing hormone type 1 receptor (CRHR1) gene. - Details in the depression lecture [Learning outcomes:] - You understand and can explain the concept of heritability - You can estimate the heritability of depression, ADHD, bipolar disorder, autism and schizophrenia. - You can describe contribution of genes and environmental factors to the etiology of complex multifactorial psychiatric disorders - You can elaborate on the concept of complex genetics and the stress -- diathesis model - You can explain biological endophenotypes and system endophenotypes and give examples - You can understand the 'Social-ecological framework', that no single factor can explain traits and disorders. That there is a dynamic interplay of multiple risk and protective factors - You can name environmental risk factors for psychiatric disorders in general - You can explain HOW environmental factors can exert their influence on the body and brain, via alterations in the stress system and via epigenetic modifications - You understand how the brain is in constant interaction with environment, society and culture via plasticity - You can explain the line of investigation of the study 'epigenetic programming by maternal behaviour' and you can interpret the graphs and figures of this study - You can explain gene-environment interactions and give some examples Impulsivity ----------- **Background on impulsivity** Impulsivity is a multi-faceted construct consisting of different behavioral phenomena. Based on neuroimaging studies in humans and preclinical work in laboratory animals we now know that the different forms of impulsivity have different underlying neurobiology and neuroanatomy. Maladaptive levels of impassivity are key to several psychiatric and neurological disorders, such as for example ADHD or addiction. Experiment: green dot = make a tap response as quickly as possible with index finger on the table. Red dot = no response!\ Ability to stop behavior that you already started is called response inhibition (example with the red and green dots, so stop make a response when red dot is seen). If you suffer from ADHD, you are poorer at stop response tasks. Methylphenidate improves response inhibition in children with ADHD in Stop Tasks. Clinical improvement in adult ADHD is associated with methylphenidate-induced dopamine release. Increase of dopamine. [The Marshmallow experiment] Study that showed that there is development in how we value reward. The children that were able to resist eating the marshmallow, are more successful in life after 40 years. Delayed discounting is when you switch to a different reward, because of things that are changing. 10 euro's today or 100 euro's next week, then 100 next month, then 100 next year. When you switch between those two it is delayed discounting. Not only inhibitory control deficits, but also motivation disturbances important in etiology ADHD -- decision making capacity. I**nhibitory control** refers to the ability to suppress impulsive responses or inappropriate behaviors. **Motivational problems** in ADHD relate to difficulty initiating and sustaining effort, especially for tasks that are not immediately rewarding (e.g., studying or completing mundane tasks). These disturbances stem partly from alterations in **dopamine pathways**, which affect how rewards are processed and anticipated. This refers to the ability to evaluate options, weigh risks and rewards, and make choices that align with long-term goals. [Multifaceted nature of impulsivity] Impulsive action -- poor inhibitory control/behavioral disinhibition.\ Motor impulsivity: acting without foresight.\ Response inhibition: inability to inhibit ongoing behavior. Impulsive choice -- impulsive decision-making. Delay aversion: distorted judgement of alternative outcomes/intolerance to delay of gratification. How to measure impulsivity (humans) Self-report measures: Barratt impulsiveness scale (BIS-11) (30-item questionnaire to assess trait impulsivity with different factors, such as attention, motor), Eyseneck impulsiveness questionnaire. Behavioral measures: stop-signal tasks/Go-NoGo tasks, delay discounting tasks. **Neurobiology of impulsivity** Neuroimaging approaches to study neurobiology in humans: fMRI: to study brain activity based on oxygen use. PET: to study receptor binding. MEG: to study brain activity based on electrical current.  No correlation between impulsive action and impulsive choice. Different brain areas are involved. The measurement tasks we use, truly measure different things in the brain. ◊ FMRI date in humans shows different brain areas are activated during the different kinds of impulsivity. ◊ Corticostriatal connectivity in impulsivity!!!!! Afbeelding met tekst, diagram, schermopname Automatisch gegenereerde beschrijving Translational approaches: animal models Data in humans is limited because of the limited research because of ethical considerations. We use translational approaches such as animal models. Rodents are frequently used because of their genetic overlap with humans. Translational toolbox with general methodologies: individual differences, pharmacology, molecular biology, optogenetics, neuroimaging. ◊ Results are similar between humans and rodents between the different tasks +-----------------------------------+-----------------------------------+ | Humans | Rodents | +===================================+===================================+ | Continuous performance task | 5-choice serial reaction time | | (target sequence -- push button) | task | | | | | - Impulsive action | - Impulsive action | +-----------------------------------+-----------------------------------+ | Stop-signal task (red and green | Stop-signal task | | dots) | | | | - Impulsive action | | - Impulsive action | | +-----------------------------------+-----------------------------------+ | Experiential delay discounting | Delayed reward paradigm | | | | | - Impulsive choice | - Impulsive choice | +-----------------------------------+-----------------------------------+ Neurochemistry of impulsivity: Monoaminergic and cholinergic pathways in the brain that play a role: acetylcholine (ACh), serotonin (5-HT), dopamine (DA), noradrenalin (NE). Serotonin system associated with aggression but also impulsivity aggression. Impulsive and not premeditated violence is associated with lower levels of serotonin metabolites. How lower the serotonin levels, the higher the correlation with impulsive aggression. Serotonin depletions increase impulsive action and not impulsive choice. So, impulsive choice is unaffected! The use of an SSRI (citalopram -- antidepressant that increase serotonin levels) therefore appeared to show an improvement in impulsive behaviour (a higher serotonin level seems to better the capacity to inhibit behaviour), but had no effect on impulsive choice Altered dopamine transporter (DAT) levels in ADHD? Dopamine and ADHD 1. Dopamine in the Reward System: - Dopamine is critical for reward processing in the brain, especially in the mesolimbic system, which includes the ventral tegmental area (VTA) and the striatum. - It regulates motivation, pleasure, and learning through reinforcement. 2. Altered Dopamine in ADHD: - ADHD is associated with differences in dopamine transporter (DAT) levels and dopamine receptor binding: - Lower binding potential: Less availability of dopamine to bind to receptors in ADHD brains compared to controls. - Reduced D2/D3 receptor binding in the VTA: Indicates altered dopamine signaling, impacting decision-making and impulse control. - Enhanced dopamine release in the striatum: Linked to higher impulsive tendencies. 3. Impulsivity and Dopamine: - Higher dopamine levels, particularly in impulsive individuals, correlate with: - Impulsive action: Acting without thinking. - Impulsive choice: Preferring smaller, immediate rewards over larger, delayed ones. 4. Amphetamines and Dopamine: - Amphetamines (e.g., Ritalin) increase dopamine levels by: - Stimulating dopamine release. - Blocking dopamine reuptake. - In ADHD: - Improves attention and control by stabilizing dopamine signaling. - Reduces impulsive action while potentially influencing impulsive choice differently depending on dose. Noradrenaline and ADHD 1. Role of Noradrenaline: - Produced in the locus coeruleus and projected into areas like the prefrontal cortex. - Regulates arousal, focus, and inhibitory control. - Fewer studies exist compared to dopamine, but evidence shows its significant role in impulsivity and ADHD. 2. Noradrenaline and Impulsivity: - Increased noradrenaline activity improves inhibitory control: - Reduces both impulsive action and impulsive choice. - Important for supporting executive function in the prefrontal cortex. 3. Atomoxetine and Noradrenaline: - Atomoxetine is a noradrenaline reuptake inhibitor (NRI): - Blocks the reuptake of noradrenaline, increasing its levels in the synapse. - Effective in reducing both impulsive behaviors: - Impulsive action: Acting without forethought. - Impulsive choice: Choosing smaller, immediate rewards. Key Implications for ADHD Treatment: - Ritalin (methylphenidate), a dopamine-based stimulant, is a first-line treatment in countries like the Netherlands. It enhances reward processing and focus by modulating dopamine activity. - Atomoxetine, targeting noradrenaline, offers a non-stimulant alternative that effectively addresses impulsivity. - Both systems interact to manage ADHD symptoms: - Dopamine pathways focus on reward sensitivity and motivation. - Noradrenaline pathways enhance attention and self-regulation. Noradrenalin and impulsivity: atomoxetine improves response inhibition. Interrelationship impulsivity and addiction. People that suffer from addiction have issues with impulsive behavior. Perhaps also the other way around, if you are impulsive, maybe you are dependent on drugs faster. 1\. GWAS and ADHD: Genetic Associations - GWAS (Genome-Wide Association Studies): These studies identify specific SNPs (Single Nucleotide Polymorphisms) associated with ADHD. - Many of these SNPs are linked to genes involved in dopamine and serotonin pathways, critical for regulating mood, behavior, and impulsivity. - These findings help pinpoint potential targets for therapeutic interventions. - Rodent Models: - Genome-edited rodents, with alterations in genes identified by GWAS, are used to study behavioral traits linked to ADHD. - These models provide insights into how specific genetic changes impact impulsivity, attention, and other ADHD-related behaviors. 2\. Pharmacotherapies for ADHD and Impulsivity A. Stimulants 1. Methylphenidate (Ritalin): - Inhibits: - 5-HTT (serotonin transporter): Regulates serotonin reuptake. - DAT (dopamine transporter): Enhances dopamine availability in the synapse. - NET (norepinephrine transporter): Increases norepinephrine signaling. - Increases focus and reduces impulsivity by stabilizing neurotransmitter levels. 2. Dexamphetamine: - Similar mechanism to methylphenidate: - Inhibits 5-HTT, DAT, and NET. - Stimulates the release of dopamine and norepinephrine, enhancing reward processing and executive function. B. Non-Stimulants 1. Atomoxetine: - Selectively inhibits NET, increasing norepinephrine levels. - Effective for impulsivity and attention regulation without stimulating effects. 2. Guanfacine: - Agonist of α2-adrenoceptors: - Enhances the negative feedback mechanism to reduce norepinephrine release. - Improves prefrontal cortex function, aiding in attention and impulse control. 3. Clonidine: - Also an α2-adrenoceptor agonist: - Reduces norepinephrine output similarly to guanfacine. - Sometimes used as an adjunct therapy for ADHD. 3\. Neurotransporter Functions in ADHD - NET (Norepinephrine Transporter): - Reuptakes norepinephrine, controlling its synaptic availability. - Blocking NET (e.g., with atomoxetine) increases norepinephrine levels, improving focus and reducing impulsivity. - DAT (Dopamine Transporter): - Reuptakes dopamine, maintaining reward system balance. - ADHD treatments like Ritalin inhibit DAT, enhancing dopamine signaling. - 5-HTT (Serotonin Transporter): - Regulates serotonin reuptake, influencing mood and impulsivity. - Inhibition of 5-HTT contributes to the efficacy of certain ADHD medications. - α2 Adrenoceptor: - Mediates negative feedback for norepinephrine release. - Activation by guanfacine or clonidine reduces excessive norepinephrine activity, aiding self-regulation. 4\. Optogenetics: A Future Approach - Principle: - Optogenetics uses photosensitive opsins to control neuronal activity with light. - Neurons genetically engineered to express opsins can be selectively activated (blue light) or inhibited (yellow light). - Light stimulation opens ion channels, depolarizing neurons and triggering action potentials. - Applications: - Current clinical trials are exploring optogenetics for retinal disorders. - Potential in ADHD: - Could enable precise modulation of brain circuits involved in impulsivity and attention. - Offers a non-invasive, highly targeted treatment option in the future.  Addiction is a brain disease I ------------------------------ **Definitions and diagnostic criteria** Drug addiction: - A substance-related psychiatric disorder characterized by a persistent loss of control - A chronic relapsing disorder characterized by obsessive craving Similarities with other psychiatric disorders, loss of control. Relapsing is part of the disorder, 85% that stops will relapse within 3-6 months. Is part of the process of the disease. 'Drug addiction' on itself is not constructed in the DSM (Diagnostic and Statistical Manual of Mental Disorders) so it is not a mental disorder, but essential elements of addiction are stored in the DSM and are called 'substance use disorder' DSM 5 criteria -- substance use disorders. A problematic pattern of use of an intoxicating substance leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period: 11 criteria. Loss of control is really important. The 11 criteria: a problematic pattern of use of an intoxicating substance leading to clinically significant\ impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:\ **1.** The substance is often taken in larger amounts or over a longer period than was intended.\ **2.** There is a persistent desire or unsuccessful effort to cut down or control use of the substance.\ **3.** A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects.\ **4.** Craving, or a strong desire or urge to use the substance.\ **5.** Recurrent use of the substance resulting in a failure to fulfil major role obligations at work, school, or home.\ **6.** Continued use of the substance despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of its use.\ **7.** Important social, occupational, or recreational activities are given up or reduced because of use of the substance.\ **8.** Recurrent use of the substance in situations in which it is physically hazardous.\ **9.** Use of the substance is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance. **10.** Tolerance, as defined by either of the following: A need for markedly increased amounts of the substance to achieve intoxication or desired effect.\ A markedly diminished effect with continued use of the same amount of the substance.\ **11.** Withdrawal, as manifested by either of the following:\ The characteristic withdrawal syndrome for that substance (as specified in the DSM- 5 for each substance).\ The substance (or a closely related substance) is taken to relieve or avoid withdrawal symptoms\... Two or three symptoms indicate a mild substance use disorder, four or five symptoms indicate a moderate substance use disorder, and six or more symptoms indicate a severe substance use disorder. Use persists in the face of extreme health consequences (smoking packages with pictures of black lungs). Key characteristics of drug addiction: - A chronic disease process that develops into relatively rigid pattern of behavior - Compulsive use of substance - Difficulty in reducing or stopping use despite recognizing the harmful consequences - High probability of relapse **Theories on addiction** What is the most *harmful* drug in our society? UK-research - harmful drug use, based on harm to others and harm to user -\> alcohol is the most harmful drug (overall harm score 72), with heroin (55) and crack cocaine (54) in second and third places. Criteria: Afbeelding met tekst, diagram, lijn, Perceel Automatisch gegenereerde beschrijving Harm to others in alcohol is around 48, to user 24. But heroin and cocaine harm is bigger to user than to others. Main findings: - Alcohol is the most harmful - Drugs-specific mortality was a substantial contributor to five of the drugs (alcohol, heroin, GHB, methadone, and butane). - Economic cost contributes heavily to alcohol, heroin, tobacco, and cannabis. But there is no correlation (0.04) with the current classification in the UK (misuse of drugs act 1971). *An act to make new provision with respect to dangerous or otherwise harmful drugs and related matters, and for purposes connected therewith.* **Class A** includes heroin, cocaine, crack, MDMA ("ecstasy"), methamphetamine, LSD and psilocybin mushrooms. **Class B** includes amphetamine, cannabis, codeine, and methylphenidate. **Class C** includes GHB, ketamine, diazepam, flunitrazepam and most other tranquillizers, sleeping tablets and benzodiazepines as well as anabolic steroids. Final statement ISCD is that aggressively targeting alcohol harms is a valid and necessary public health strategy -\> one of his outcomes. Alcohol is not in the classification system. What is the most [addictive] drug in our society? Prevalence of drug use and dependence -- when you start smoking, 1 out of 3 become addicted. Nicotine has the highest risk of recreational use to dependence, then heroin, cocaine, alcohol, cannabis and mushrooms. In the Netherlands the drug use is also the highest for alcohol and tobacco and the same for dependence. Most people die from tobacco use. Disability adjusted life years are calculations of risk factors that cause a chance of a reduced lifespan and/or diseases. Nicotine is the second biggest risk factor; a smoker, for example, loses 13 years of his life. **Views on Addiction** Drug-centered view on addiction - Drug is the driving force Three different views within the drug-centered view: [Negative reinforcement/anhedonia view] Addiction behavior is maintained because the aversive symptoms associated with withdrawal are alleviated by the drug. Drugs are sometimes used to 'self-medicate', relieving pre-existing symptoms such as pain, anxiety or depression that occur in life independent of drug use. Shortcomings of this view: Drugs are self-administered in the absence of withdrawal symptoms (need to take the drug for longer period). There is little correlation between the seriousness of withdrawal (afkickverschijnselen) signs and their motivational force in maintaining addictive behavior. There are many drugs used medically that produce withdrawal syndromes but are not typically self-administered for non-medical purposes. Relief of withdrawal is minimally effective in treating addiction. High tendency to relapse long after withdrawal symptoms have subsided. [Positive reinforcement/euphoria view ] Addiction behavior is maintained because of the euphoric state drugs induce, not because they alleviate an unpleasant state. Drugs act as a positive reinforcer because they produce pleasure and are therefore addictive. Shortcomings of this view: No clear relationship between the ability of drugs to produce euphoria and their addictive potential. Negative consequences of continued drug use seem enormous relative to the pleasure effect. Drug taking can be maintained in the absence of subjective pleasurable effects (difference between liking and wanting/needing). [Neuroadaptation model (leading hypothesis)] Addictive behaviour is caused by progressive and persistent changes in the brain (neuroadaptations) resulting from repeated drug or alcohol consumption. The neuronal system mediating the motivational effects of drugs gradually becomes hypersensitive to drugs and drugs-associated environmental stimuli (cue's). this sensitization phenomenon makes drugs increasingly attractive, leading to obsessive craving for the drug effect, compulsive drug-seeking and relapse to drug consumption. The development of addictive behavior represents a pathological learning process and relapse is caused by retrieval of drug-associated information that is persistently stored in the brain (memory). The neural system in the brain that is altered by addictive stimuli and mediates addictive behaviour is the mesocorticolimbic system. **How do drugs act on the brain?** [Drugs activate the brain reward system (dopamine system)] Much more addictive when it affects the dopamine system. There are drugs that activate the serotine system, but these are hardly addictive. The brain\'s reward system is a network of structures that reinforce behaviors essential for survival and provide pleasure or satisfaction. Central to this system is the role of dopamine neurons located in the ventral tegmental area (VTA). Here's a more detailed explanation of the concepts: 1\. The Brain\'s Reward System - The reward system is responsible for reinforcing behaviors that are beneficial for survival and reproduction. Activities like: - Sex and eating trigger dopamine release, making these behaviors pleasurable and encouraging repetition. - Survival-critical functions: The reward system ensures focus on activities vital to survival. - Drugs of abuse hijack this system\*\*: - Substances like nicotine, cocaine, and opioids stimulate dopamine release in ways far exceeding natural stimuli, leading to euphoria and addiction. 2\. Dopamine\'s Role in the Reward System - Dopamine Neurons of the VTA: - The VTA projects to key areas like the nucleus accumbens, prefrontal cortex, and amygdala, forming the mesolimbic and mesocortical pathways. - Dopamine released in these areas creates a sense of reward and reinforcement. - Release Mechanism: - Dopamine is stored in vesicles in the presynaptic neuron. - When a reward or drug stimulus occurs: 1. Dopamine is released from the vesicle into the synaptic cleft. 2. It binds to dopamine receptors (D1-like or D2-like) on the postsynaptic neuron. 3. This activates the brain\'s reward circuits. - Reuptake to Regulate Dopamine Signal: - Once the signal is transmitted, dopamine must be cleared from the synaptic cleft to prevent overstimulation: 4. Reuptake Carriers (e.g., DAT): Transport dopamine back into the presynaptic neuron. 5. Dopamine is either: - Repackaged into vesicles for future use by VMAT2. - Degraded enzymatically by MAO and COMT if excess. Cocaine blocks the reuptake of dopamine (receptor has a binding side for cocaine) DAT is responsible for reabsorbing dopamine from the synaptic cleft back into the presynaptic neuron after dopamine is released. By blocking DAT, cocaine prevents dopamine reuptake, allowing more dopamine to remain in the synaptic cleft for an extended period. Enhanced dopamine transition. Can repeatably bind and activate the dopamine receptor on the post synaptic cleft. Which leads to enhanced dopamine transmission -\> intense feelings of reward. This is partly the reason for the addictive potential. THC (cannabis) activates (disinhibits) the dopamine neurons indirectly. Dopamine neurons are activated through a THC receptor (CB1 receptor). \- THC activates (disinhibits) the dopamine neurons indirectly (via GABA) \- We have CB1 receptors because we also have our own cannabis that are important in pain, excitement, learning. - Most abandon receptor we have in our brain - Reduces the release of GABA, and with less GABA to inhibit dopamine neurons, the firing rate goes up. - Firing rate goes up -\> more release of dopamine CB1 receptors are located primarily on GABAergic neurons and glutamatergic neurons, but not directly on dopamine neurons.  Opiates (morphine) activate (disinhibit) the dopamine neurons indirectly (via GABA). Opiate receptors where opiate binds, we have a receptor because we also have our own opiates in our body.\ Is located on the GABA neuron, GABA normally inhibits the neurotransmission, but when opiates activate their receptor, GABA function does not work anymore. Then there is more release op dopamine and thus longer activation of the brain reward system. Over time, the brain adapts to this overstimulation, reducing dopamine receptor sensitivity and leading to **tolerance** (requiring more of the drug for the same effect). Nicotine receptor activation results in release of dopamine. Nicotinic receptors, we have different types. If nicotine activates the nicotinic receptor/channel it releases sodium. \- We have nicotine receptors in the brain (high affinity) \- 5 subunits of proteins that make a pore where sodium can go through and depolarize -\> activate the cell directly \- Nicotine binds to nicotinic acetylcholine receptors in the CNS -\> release of dopamine \- A lot of different type of nicotine receptors throughout the whole body \- The nicotine receptors in the brain have different compositions -\> Alfa 4 Beta 2 construction is very important for the activation of the dopamine system. So, depolarizing of the cell (sodium channels) results in the release of dopamine. If we would create humans without Beta 2 through gene therapy, it would solve the problem of nicotine addiction. But Beta 2 increases the focus and attention, so you take away the natural and positive aspects from the nicotine Alcohol interacts with several receptors in the brain. We don't have an alcohol receptor. Variety of receptors that it can activate. GABA, block glutamate receptors, effect on the nicotine receptor (can be why it is mostly used together). Afbeelding met tekst, schermopname, grafische vormgeving, cirkel Automatisch gegenereerde beschrijving We do not have a receptor for alcohol. It is a very small molecule and can affect the membrane and have a direct effect on membrane potential. It has also several effects on several different receptors in the brain - Alcohol interacts also with the nicotinic acetylcholine receptors which explains why alcohol and smoking are co-abused and it is hard to fix this. - Alcohol can activate the endogens opiates. It can inhibit the release like the opiates does - Interaction with several receptors in the brain. Inhibited action of glutamate at NMDA- receptors by blocking these receptors (-) Inhibited action of glutamate at kainite receptors (-) Inhibition of voltage-sensitive CA2+ channels (-) Enhances GABA action at GABA-A receptors (positive allosteric modulator) - Enhanced action of 5-HT at 5-HT3 receptors (+) Enhanced action of acetylcholine at nicotinic acetylcholine receptors (+) \- \> All these actions together from alcohol leads to activation of the dopamine rewards system \- Direct: Alcohol can directly increase the activity of dopamine neurons \- Indirect: Acute alcohol can induce β-endorphin release, resulting in activation of μ receptors on the GABAergic neurons in VTA. This, in combination with alcohol's inhibition of glutamate effects on GABA neurons, could lead to decreased GABAergic activity in the VTA, and subsequently increased firing of the dopaminergic neurons, resulting in increased dopamine release in the nucleus accumbens (NAc). **How do drugs change the brain?** Experiment on rats with fonzies (candy) and morphine. Morphine highly increases your dopamine release (alcohol, heroin, nicotine). Natural reward doesn't activate this amount of dopamine as addictive drugs can. It activates it much stronger. When you have a stimulus that activates the brain in such high amounts, your brain will remember this. Repeated morphine results in long-lasting morphological changes in neurons of the reward system. Change in spine density in prefrontal areas 1 month after amphetamine SA. Natural reward won't give the same response. Long-term structural changes because of self-administration of the drug. Has consequences of the function of these brain areas (cognitive capacities). Cortical thickness differences in young adult smokers compared with nonsmokers (humans). Insular is important region in smoking addiction, when people have damage there because of an accident, we see that people can stop smoking instantly. Reduction in cortical thickness relates to dependence severity and cumulative intake. People that are more dependent on nicotine, the higher the score. Pack-year is one year where you smoked a package of cigarette a day. The more nicotine, the more effects on the cortical thickness of your brain. Addiction is a brain disease II ------------------------------- [Novel treatment options] New therapies should help to restore brain organization altered by addictive drugs. Two examples: - Molecular basis of relapse - Erasing drug memories Current therapies are not aimed at restoring brain organization but aimed at preventing symptoms or reducing the symptoms. [Relapse] Is often preceded by craving and can be elicited by: - Drug-associated cues (environment, paraphernalia). Addicts are very sensitive for them and can rigger relapse. - Drugs of abuse - Stressful stimuli 4 fast photos on the screen -- exposed us to very short time periods. For severe addicts is it enough to activate his brain reward system. We are not aware of those cues, because was really short. But addicts can feel craving and don't even know where it came from. Doesn't activate the prefrontal cortex yet, only the brain reward system. The control system in your brain is not activated and that makes you very vulnerable to relapse under these conditions. The drug itself can induce craving. Just one drink or cigarette can escalate his behavior already, can trigger to do it more. Animal models in which we can mimic the brain mechanisms behind relapse. Rats or mice have the same reward system in our brain, so they are sensitive to drugs of abuse. They will self-administer all the drugs that we like. The animal must make a response to do that, so instrumental learning. In this case, two holes where the animal must poke his nose through. One hole delivers the drugs and the other doesn't deliver anything, so we could see if the animal learned the trick. Every time he pokes his nose and receives a reward then there is a light that goes on for a few seconds and he hears a sound. Tone-light combination that is associated with each drug delivery -\> use it to trigger a relapse. Self-administer the drug and then we take away the drug and the cues, which they go in the extinction fase (rehab). Tone-light combination reintroduced and then the animal starts responding. He wants to have the drug again, but he doesn't get it, we are looking at his motivation to find the drug. Looking at seeking behavior. We also do this with cues, stress or priming.  Incubation of craving -- gradual increase in cue-sensitivity during cocaine abstinence. Used the same study, so self-administration of cocaine for period. Then looked at the response in the days of abstinence -- respond on a lever that previously was associated with cocaine. We see that the longer the animals were abstinence, the more sensitive they were to the cues. Every time they made a response on the lever, the queued light came on that was associated with cocaine. The longer you are abstinence you are from the drug, the more sensitive you become to those drug associated cues. We call this *sensitization.* Mimic this study on humans with smokers. Exposed the ex-smokers to neutral cues or smoking cues to elicit craving. You see the change in abstinence day 14. You see a delay in craving, incubates over time. [What is going on in the brain] The medial prefrontal cortex (mPFC) seems to be very sensitive to those cues. Brain imaging study done in heroin addicts that were abstinent. Put them in the scanner and someone was reading an audio taped autobiographical script of an episode of craving. It will elicit craving and the medial prefrontal cortex changes in activity. Area that is changing when a patient is exposed to cues in different ways -\> drug memory is stored here. Did the same animal model to investigate the changes in the mPFC. In this case they received heroin every time they poked their nose. Then extinction, re-exposing and relapse behavior. Synapses where neurotransmission takes place, usually when something goes wrong in the brain it is at the level of neurotransmission. Looking at these synapses that could explain why these animals are relapsing. Saw some changes in two proteins. AMPA receptor that is sensitive to glutamate. We see that upon cue exposure there is a down regulation of these proteins that's formed the receptor. Strength of the synapse can be changed by changing the receptor composition (stronger synapse have more receptors). Observed that there are less AMPA receptors after exposure and increase protein that is taking care of the internalization of these receptors. -\> synapse becomes weaker. Used peptide that could block internalization of these AMPA receptors. Greatly reduced the responses during the test. Reduced heroin seeking. So, internalization of these glutamate receptors plays a role in relapse. Nucleus accumbens is the reward center and normally we see that the prefrontal cortex tries to suppress the reward center what we call cognitive control, stop-signal of the brain. Stop-system becomes weaker because the glutamate receptors are removed from the synapse. Prefrontal cortex projects with glutamate to the nucleus accumbens. Upon cue exposure, it will lead to a weaker control, a weaker inhibitory control over heroin seeking. -\> not possible in humans. [Models of memory processing] Afbeelding met tekst, Lettertype, schermopname, ontwerp Automatisch gegenereerde beschrijving - Traditional consolidation theory -\> Lewis' memory model (1979) Short term memory you are still sensitive to disruption, when it comes consolidated into long-term memory it is relatively insensitive to disruption. Lewis states that memories can be in two different states. Active: you think about something, then that memory becomes active -\> sensitive to disruption. Reconsolidated it becomes stable. When memory is retrieved and in an active state there is a reconsolidation window in which the memory can be manipulated until it is completely reconsolidated. We believe that the time window is about six hours -- you can try to disrupt the reconciliation, opportunity to manipulate memories within these six hours. Glutamate receptor (NMDA) and receptor that is sensitive to nor adrenaline (Beta adrenaline receptor) are critical for the reconciliation process. If you give the animal a drug that blocks either beta receptor or NMDA receptor, you can disrupt reconciliation process and reduce for example fear. Some of these drugs are available to human use -\> propanol. [Procedure we call extinction procedure:] To prevent drug craving in heroin addicts -- erase a drug memory. Group of heroin addicts that they exposed to three treatment protocols. Looked at their baseline craving (measure craving). Divided into 3 treatment groups and wanted to reactivate the heroin memory (heroin cues). Control group got neutral cues.  After the procedure, you see that the group that received the retrieval and extinction procedure, they show much less craving when exposed again to cues. This effect was not seen in the group that received the procedure, six hours after the retrieval phase, so after the reconstruction window. When people have 5 minutes retrieval, 10 minutes wait-time and 60 min extinction, the craving change score is the highest when heroin cues are giving. [Why do some people become addicts and others not?] Only a proportion of those who have experience with drugs will become dependent on a drug. 15% crossover or 20 perhaps that will come dependent. Look at the first risk factor: genes. *Genes* A = influence of genetic factors (heritability) C = influence of shared environment E = influence of unique environment Heritability based on twin studies Large proportion of smoking is explained by common environmental factors. Relatively small proportion is due to genes -- 35%. -\> in start smoking. But when you are dependent on smoking, the genetic contribution is quite large -- 75%. Start smoking is your environment, but whether you get dependent or not is very much dependent on genes. *Genetic dependence* Alcohol -- 50-70% Nicotine -- 50-75% Cannabis -- 35-75% Cocaine -- 35-80% Heroin -- 40-60% [Genetic predisposition] Doesn't say which genes are involved, only that there are genes involved. - Genome Wide Association Studies (GWAS) have indicated that alcohol and tobacco use disorders are associated with many genetic variants. - They provide evidence for the involvement of many systems in tobacco and alcohol use disorders, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. - There is overlap in genes associated with alcohol abuse and those associated with use of other drugs and other psychiatric problems (ADHD, schizophrenia, depression). Comorbidity between different psychiatric problems. Interaction of many genes and then with the environment that makes you vulnerable to become addicted. Co-morbidity and risk-factors in drug abuse -- addiction almost never comes alone: - Mental disorders: depression, anxiety disorder, PTSD, ADHD, psychotic disorders and OCD. - Personality traits: antisocial/aggressive (CD), sensation seeking and impulsivity. - Learning disability [Neurobiology of the individual differences] Does a person that is more vulnerable to become addicted a different brain? Low D2/3 binding is associated with drug liking. Study where they asked healthy volunteers without an addiction to take Ritalin. Ask them how much they liked the drug (euphoric abilities). People put in a scanner, used a tracer to see how much the availability is of the dopamine receptor. Strong correlation between how much you liked the drug and how much of these receptors you have in the brain. The more the receptor in the brain, the less you like that drug. Lower availability, you like the drug very much. That means that whether you like the drug or not is already carved in your brain. Reduced dopamine D2/3 receptor availability in the ventral striatum of impulsive rats. Animals that are high impulsive also show less dopamine receptors in their ventral striatum. Interesting because we already know that impulsivity is a risk factor. Measuring impulsivity in rodents -- 5-choice serial reaction time task. Measures attention and impulsive action. ADHD ---- Which 3 words would you choose to describe ADHD symptoms? (DSM criteria): - Inattention - Hyperactivity - Impulsivity 2-5% children aged 6-16. 80% boys and symptoms persist into adulthood 30-50%. [Neuroimaging findings] Which brain structures could be impaired in people with ADHD? - Prefrontal cortex (less inhibitory control, more impulsive) - Cerebellum & caudate nucleus (motor hyperactivity) - Corpus callosum (less communication hemispheres) BUT most imaging studies underpowered (less than 20 subjects in group) Largest study of date of brain volume differences between participants with ADHD and healthy individuals (worldwide collaboration; 23 cohort studies, n=3242, 1713 participants with ADHD and 1529 healthy controls. Study newly identified amygdala, accumbens, and hippocampus volumes to be smaller in participants with ADHD than in healthy controls. Replication earlier findings for reduces caudate and putamen volumes. Largest effect in amygdala: also, in ADHD to emotional regulation problems (difficulties in recognition of emotional stimuli, diminished emotional reactions to pleasant stimuli, and high levels of callous, unemotional traits). Emotional regulation problems often present in patient with ADHD, but these disease characteristics have not (yet) been included into the official DSM criteria. Volume differences clustered in children and no differences at group level were reported in adults. Most pronounced effects in childhood + delayed peaks of subcortical volume maturation: model of ADHD as a disorder of brain maturation delay. 'Our findings contain several important messages for clinicians. First, the data from our highly powered analysis confirm that patients with ADHD do have altered brains and therefore that ADHD is a disorder of the brain. This message is clear for clinicians to convey to parents and patients, which can help to reduce the stigma that ADHD is just a label for difficult children and caused by incompetent parenting. We hope this work will contribute to a better understanding of ADHD in the general public, and that it becomes as apparent as major depressive disorder, for example, that we label ADHD as a brain disorder.' Criticism: small effects, only group level, heterogeneous, stigmatizing. Author's reply to criticism: "no claims about causality" Future goal of authors: develop growth curve of the brain (similar to body weight) [Genetic factors] From twin + adoption studies: several behavioral traits and psychiatric diseases moderate / high heritability. Heritability = proportion of variance in symptoms that is explained by the variance in genetic factors. Major depression heritability = 40-50%. ADHD = 75%. Autism, bipolar disorder, schizophrenia around 80%. In post -- 'human genome project' era was the expectation that it is easy to find risk genes. Contrary is true, because it is very difficult. Got the 'missing heritability' problem. Model of single / few risk genes = overly simplistic paradigm. Heritability of ADHD is 76%. Genome-wide association is largely inconclusive. *Weak* association with DAT gene and DRD4. These genes account for only about 3% of phenotypic variation. This suggests that many unidentified common variants with small effects, gene-environment or gene-gene interactions, rare variants, or a combination of these factors play a prominent role in the genetic cause of ADHD. [Non-genetic factors] Non-genetic factors are also associated with ADHD. For some: evidence for these associations are probably causal.Afbeelding met tekst, schermopname, Lettertype, document Automatisch gegenereerde beschrijving [ADHD treatments -- medication] Dysfunctions of dopamine NT system (hypodopaminergic condition). Methylphenidate and (dex)amphetamine. Block reuptake dopamine (DAT inhibitors). Increase DA concentration. BUT: oversimplification Behavioral therapy: How effective is treatment? Multimodal Treatment Study of Children with ADHD (MTA) by US National Institute of Mental Health. Largest longitudinal study in child psychiatry, 579 children aged 7-9, random in 4 treatment groups. [MTA] - Standard community care (treatments by community providers) often with prescribed medication (no treatment from NIHM). - Intensive behavioral therapy without medication (BT). - Intensive carefully tailored medical treatment with accompanying counseling for child and parents (MED). - Combination medication and behavioral therapy (COMB).Afbeelding met tekst, Lettertype, schermopname, Publicatie Automatisch gegenereerde beschrijving All 4 groups showed sizable reduction in symptoms over time. For most ADHD symptoms, children in COMB and MED (medication management groups) showed significantly greater improvement than those given intensive BT and community care. Study medication strategies were superior to community care treatments, despite the fact that two thirds of community-treated subjects received medication during the study period. COMB and MED management treatments did not differ significantly on any direct comparisons for core ADHD symptoms. But COMB proved superior for non-ADHD (according to DSM) symptoms and positive functioning outcomes (oppositional/aggressive symptoms, internalizing symptoms, teacher-rated social skills, parent-child relations, and reading achievement). 8 years later a follow-up study: - There is symptom improvement that is largely maintained after treatment - In nearly every analysis, the 4 groups did not differ significantly on repeated measures or newly analyzed variables (e.g., grades earned in school, arrests, substance use, psychiatric hospitalizations, other clinically relevant outcomes). - Intensive state-of-the-art treatments (COMB, MED, BT) no long-term benefits. Conclusion of ADHD researcher Volkow: 'one recommended strategy is to temporarily discontinue the medication after 1 or 2 years of treatment to determine whether benefits are lost; a loss of benefits would suggest that the medication is still useful'. [Long term effects on gray matter volume] ADHD medication any effect on brain abnormalities? Structural: gray matter volume (MRI). Functional: inhabitation and attention tasks (fMRI). Conclusion of gray matter volume in ADHD study: these findings confirm that the most prominent and replicable structural abnormalities in ADHD are in the basal ganglia. They furthermore suggest that ADHD patients may progressively catch up with their developmental delay with advancing age and that use of stimulant medication may be associated with normalization of structural abnormalities in ADHD, although longitudinal studies are needed to conform both observations. - Use of stimulant medication may be associated with normalization of structural abnormalities in ADHD. - But! Advancing age is also associated with normalization of structural abnormalities in ADHD - But: longitudinal studies needed! - Recent large Dutch mega-analysis study could not replicate these results. Another study about subcortical brain volume differences in participant with ADHD in children and adults: cross-sectional mega analysis - 'Psychostimulant medication no influence on brain area volumes' - 'Because our study had a non-randomized, cross-sectional design, some caution in the interpretation of these results is warranted because the design of this study was not optimal to test for medication effects'. - 'Because both previous meta-analyses used voxel-wise maps \[technique 1\], there is a possibility that the observed normalizing effects of medication were too local to be picked up by volumetry \[technique 2\]. - Long-term damage is not seen Meta-analysis of fMRI studies of inhibition and attention in ADHD. Conclusion: patients with ADHD have consistent functional abnormalities in 2 distinct domain-dissociated right hemisphere front-basal ganglia networks, including the inferior frontal cortex, supplementary motor area, and anterior cingulate cortex for inhibition and dorsolateral prefrontal cortex, parietal, and cerebellar areas for attention. Furthermore, preliminary evidence suggests that long-term stimulant medication use may be associated with more normal activation in right caudate during the attention domain. - Use of stimulant medication may be associated with more normal activation in the caudate nucleus during an attention task. - But! Advancing age is also associated with normalization of functional abnormalities in ADHD. - But: more longitudinal studies needed. [Stimulant medication] Medication efficacy, no long-term brain damage -- any other side effects? Mechanism of action methylphenidate resembles that of cocaine. Amphetamine is also used as illegal drug ('speed'). Negative consequences of stimulants? Substance abuse / dependence. Growth inhibition. **Substance abuse / dependence** Meta analysis 2003: stimulant therapy in childhood associated with reduction risk drug and alcohol disorders later on.  However, since then, these results could not be replicated. 2008: findings revealed no evidence that stimulant treatment increases or decreases risk for subsequent substance use disorders in children and adolescents with ADHD when they reach young adulthood.Afbeelding met tekst, schermopname, Lettertype, document Automatisch gegenereerde beschrijving Now: some studies DO find beneficial effects of stimulant medication Caution: preliminary results, 'open label' studies.  In the last decade, there have been published several studies in humans (meta-analyses or original investigations) that found either a no effect of stimulant medication on future drug use and drug addiction or even a beneficial effect. as concluded by Hammermness (2017): 'Well-monitored stimulant treatment may reduce risk for alcohol and substance use in adolescent ADHD.' This is even more important and relevant, because ADHD as a condition in itself increases probability of substance use disorders later on in life \[co-mobitity\]. *Substance Use Disorders (SUDs) are medical conditions that involve the compulsive use of substances---such as alcohol, drugs, or prescription medications---despite the harmful consequences on a person's health, relationships, and ability to function. These disorders are characterized by an inability to control substance use, strong cravings, and continued use even when it leads to serious problems at work, school, or home.* **Effects of stimulant medication on growth** Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. Average growth of 2.0 cm and 2.7 kg less than the not medicated subgroup. No evidence of growth rebound. [Concluding remarks] - Complex problems do not have easy, straightforward, black-and-white solutions. - Scientific evidence is changing constantly - Good methodological design + replication = extremely important - Check recent findings + meta-analysis - As a scientist and as a human always be willing to change your opinion if evidence changes. [Learning outcomes] - You know which brain areas are impaired in people with ADHD - You can explain the concept of disorder of brain maturation delay - You can estimate the heritability of ADHD - You know the names of ADHD medications and you can explain the working mechanism (dopamine reuptake inhibitors). - You can make a global estimation of the efficacy of different treatment options (therapy, medication) - You can explain the long-term effects of ADHD medication on growth, risk of substance misuse/abuse, brain area volumes (MRI) and functional connectivity (fMRI). Neurodiversity for ASD & ADHD ----------------------------- Awareness behavioral and personality traits and disorders exist along a spectrum. Impulsivity, mood, gender identity, risk-taking behaviour, intra/extra-version, openness, (anti) social behavior, stress-sensitivity, resilience and vulnerability. Border between normal and abnormal behavior? Border between 'health' -- 'dysfunction' -- 'disorder'? [Introduction to Psychiatric Conditions] When does personality trait become 'psychiatric disorder'? For classification and diagnosis. DSM 5 -- Diagnostic and Statistical Manual of Mental Disorders. DSM-IV & DSM-5: categorical diagnosis \> either you have psychiatric disorder ('ill') or not ('normal). For some diseases categorical diagnosis is logic: a disease state that is qualitatively separable from the state of being 'well', for example, tuberculosis or leukemia. Many psychiatric disorders might be better conceptualized as dimensional or spectrum traits. DSM-5: Autism Spectrum Disorder (ASD) is NOW finally approached in a spectrum/dimensional way. Reaction from high functioning autistic people: concept of neurodiversity (1998). 'There is a diversity among human brains regarding sociability, learning, attention, impulsivity, mood and other important mental functions'. Neurodivergent vs. neurotypical. Concept of neurodiversity \> regular scientific journals such as Nature. Laurent Mottron is a professor and hold chair in cognitive neuroscience of autism, eight autistic people in his group: four research assistants, three students and one researcher. ADHD & ASD are generally described in negative ways: - ADHD: overly active, low concentration, low impulse control, easily distracted. - ASD: impaired social relationships, strange behaviors, narrow interests. But emphasis could also be placed on the more positive aspects of the conditions. Advantages: - ADHD: spontaneous, creative, divergent mind, vital, high-energy, fast thinking. - ASD (level 1): strong persistent interests, attention to detail, unusual memory, fascination with systems and patterns, and ability to concentrate for long periods. Growing body of research: high functioning autistics outperform neurologically typical children and adults in a wide range of perception tasks: - Spotting a pattern in a distracting environment - Auditory tasks (such as discriminating sound pitches) - Detecting visual structures and mentally manipulating complex three-dimensional shapes - Raven's Matrices (a classic intelligence test in which subjects use analytical skills to complete an ongoing visual pattern) - Simultaneously process large pieces of perceptual information, such as large data sets. Neurodiversity in practice: be aware of your mental condition, strong points, pitfalls, adjust life and surroundings to your unique qualities ('Niche construction'), what would be niche construction for ADHD & ASD? Niche construction for ADHD: - Choose job: being out in nature, travelling or moving around frequently, working with one's hands, handling emergencies, being physically engaged, doing many different things in short period of time. - Use smartphone for organizing and managing daily schedule - GPS tracking / AirTag keys, wallet (because frequently misplacing items, this reduces stress) - Behavioral Therapy chatGpt: In this context, **niche construction** refers to creating or choosing an environment that aligns with and supports an individual's natural traits, abilities, and needs, specifically tailored to someone with ADHD. For individuals with ADHD, niche construction involves structuring their lives and work environments in ways that reduce potential challenges and leverage their strengths. Niche construction for ASD: - Choose job: solitary work, science or IT, working with large data sets, jobs high concentration. - Use (cognitive) behavioral therapy to learn and understand social relationships. - Connect with like-minded people via internet for support and understanding. Pitfall neurodiversity = romanticizing psychological/psychiatric conditions. Advantages by ADHD, bipolar disorder and high-functioning autists. Almost NO advantages for individual in case severe depression and schizophrenia: severe brain disorders with negative consequences for individual and surroundings. **Learning outcomes** - You are aware that personality traits (functional and pathological) exist along a spectrum / continuum - You can elaborate on the concept of neurodiversity in your own words - You can apply neurodiversity and 'niche construction' for psychiatric conditions (high-functioning autism, but also depression and ADHD). Week 2: Cognitive enhancers, deep brain stimulation & eating disorders ====================================================================== Introduction to (ab)normal behavior ----------------------------------- The following criteria/definitions are used to determine\ whether a person's behavior is abnormal or not:\ - Deviation from statistical norms\ - Deviation from social norms\ - Maladaptiveness of behavior\ - Personal distress *Deviation from statistical norms* Abnormal means 'away from the norm'. abnormal behavior would be any that is statistically deviant. Most people fall within the middle range of for example height, weight, intelligence. All extremes are considered abnormal. It fails to recognize the desirability of the particular behavior. Example: if the majority of a population smokes, then smoking is the norm and not smoking is abnormal. *Deviation from social norms* Every culture has certain standards for acceptable behavior. Behavior that deviated from that standard is considered to be abnormal behavior. Example: it is common in Southern Europe to stand much closer to strangers than in the UK. It is not prevalence of the behavior that makes it (ab)normal, but the perception of it by others. Problem: standards can change with time and can vary from one society to another. Example: drinking and driving was once considered acceptable but is now seen as socially unacceptable, whereas homosexuality has gone the other way. *Maladaptiveness of behavior* How does the behavior affect the well-being of the individual and/or social group? Examples: a man who attempts suicide, an alcoholic who drinks so heavily that he or she cannot keep a job or a paranoid individual who tries to assassinate national leaders. But also, a young boy that cannot sit still in a classroom. Limitations of this definition is that particular behavior may be harmful/not accepted in some situation, but actual be helpful, functional and adaptive for the individual in other situations or circumstances. *Personal distress* Considers abnormality in terms of the individual's subjective feelings, personal distress, rather than his behavior. If a person feels uncomfortable in situations where others do not, then that person may be maladjusted. Definition of mental disorder: any behavior or emotional state that causes an individual great suffering or worry, is self-defeating, or self-destructive, or is maladaptive and disrupts the person's relationships or the larger community. Obesity -- body weight regulation, pathophysiology and treatment ---------------------------------------------------------------- [Learning objectives] - Name three brain regions/circuitries that are important for regulation of energy homeostasis, and shortly describe how they integrate information to regulate energy balance - Name at least three hormones / neurotransmitters / neuropeptides that are involved in energy homeostasis - Understand how leptin resistance works - Understand how impaired melanocortin signaling can result in obesity - Name several strategies for body weight loss/control [Obesity epidemic ] Change in obesity prevalence worldwide. *How do we measure deviations in body weight (homeostasis)?* BMI = weight (KG)/height(m^2^). Other measurements: body adiposity index, waist circumference measurement, waist-to-hip ratio, body fat measurement. Normal \< 25 kg/m+^2.^ Overweight between 25 and 30 Obesity \> 30 kg/m+^2^ Almost more than 50% above 18 is overweight in the Netherlands. *How does one become overweight or obese?* If the balance between energy intake and expenditure is not right. If we take more energy (eating and drinking more), but do not increase our energy expenditure we gain weight. If we expenditure more energy (working out for example), but do not take more energy in, we lose weight. When in balance, our weight stays the same. Modern-day lifestyle -- we sit a lot and bad food is cheaper. We have high general sedentary (zitten) behavior and a high general caloric intake. *Changes in caloric intake in humans* Sugar-sweetened beverages are increased over time in children, but also in adults. Milk is decreased in children, because we thought we needed it to grow bones, but this is not the case. So, milk consumption decreased in children, but sugar-sweetened beverages are increased, a lot. We are eating bigger meals, and we have more snack behavior, which means more calorie intake. Physical intake is decreased in general. We started in 1965 with 235 MET-hours per week. MET = metabolic equivalent of task = a measurement for how much energy a specific physical activity cost. In 2020 we are around 142 MET-hours per week, and we predict that in 2030 we are at 126 MET-hours per week. So, we are less active and sitting more. Obesity comes with health issues, and this costs our world a lot. The 10 health problems that are linked to obesity are the following: type 2 diabetes, heart disease, sleep apnea, stroke, hypertension, osteoarthritis, certain cancers, severe COVID-19 complications, pregnancy problems and digestive problems. It costs the society billions of dollars. [Obesity neurobiology] To prevent or treat overweight we need to understand how body weight regulation goes wrong during these conditions. *Causes of obesity* It's actually many biological, environmental, and societal factors.  There are genes involved, but also social media, environment, how do you sleep, are you in pain? A lot of factors play a role. *Are the current obesity rates caused by genetic drift/selection?* No, the rising obesity prevalence is so huge that it is not possible that it is because of genetic drift. Afbeelding met tekst, kaart, schermopname, grafische vormgeving Automatisch gegenereerde beschrijving *Is obesity genetically encoded? Do 'bad' genes cause obesity?* Heritability estimates: 60-80%. Adoptee studies showed that BMI of the adopted individual was highly correlated closest with the biological parents' BMI. Example of Jennifer and Karen -\> they are identical twins and born with genes that absorb fat twice as fast as the average person. Jennifer eats healthy low-fat food and thus obesity genes are not triggered. Karen eats fatty unhealthy food and thus obesity genes are triggered. You still need an obesogenic environment to develop obesity. -\> need the unhealthy environment. [Role of epigenetics ] If the parents have a high-fat diet this renders offspring more susceptible to developing obesity and diabetes. The epigenetic inheritance of acquired metabolic disorders may contribute to the current obesity and diabetes pandemic. \> small RNAs, methylation and histone modification. *GWAS* Paper that says: several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity. GWAS confirms that CNS is important for development of obesity. Another paper: together, our results suggest that brain nuclei regulating integration of sensory stimuli, learning and memory are likely to play a key role in obesity and provide testable hypotheses for mechanistic follow-up studies. [Caloric intake ] Brains of people with obesity do not sufficiently register that there is food in their stomach.  Intake when hungry, stop when satiated -\> **homeostasis/allostasis system.** Is regulated in hypothalamus and is the homeostatic circuity. Intake without being hungry -\> motivation reward -\> **overeating.** Is regulated by striatum and is the reward circuity. These are not separate circuities but are connected. The striatum is connected to the hypothalamus, and the reward circuity also with the hunger/satiety circuity. *Hypothalamic areas important for homeostatic regulation of feeding.* Afbeelding met tekst, diagram, schets, Lijnillustraties Automatisch gegenereerde beschrijving In 1940 there were ventromedial hypothalamus (VMH) lesions in rats. Example with rat that had the VMH lesion and weights 988 g and same-aged control rat weighing 312 g. Ventral medial hypothalamus (VMH) = satiety center? Lesions of the lateral hypothalamus (LHA) results in underweight/starvation. Lesions of the VMH results to overweight/obesity. Different parts of hypothalamus play different roles in eating behavior. *Leptin discovery* In 1994 there was a discovery of leptin in animal models.  *Explanation gpt for fat tissue importance and leptin:* Fat tissue plays a significant role in brain function, especially in the regulation of energy balance, food intake, and energy expenditure. Here\'s how it is connected: **Leptin and its Role in the Brain** Leptin is a hormone produced by fat cells (adipose tissue). It acts as a crucial signal to the brain, particularly the **hypothalamus**, which is the brain region that regulates hunger and energy homeostasis. When fat stores increase, leptin levels in the blood rise. These increased levels signal to the hypothalamus that the body has enough energy stored, leading to **reduced appetite** and **increased energy expenditure**. Conversely, low leptin levels, such as in cases of low body fat or leptin deficiency (like in Ob/Ob mice), signal to the brain that the body needs more energy, which **increases hunger** and **decreases energy expenditure**. **Leptin Resistance** In obesity, despite high levels of leptin due to increased fat stores, the brain may become **resistant to leptin**. This condition is known as **leptin resistance**, where the hypothalamus no longer responds adequately to leptin\'s signals. As a result, the brain mistakenly thinks the body is in a state of starvation, which leads to **increased food intake** and **reduced energy expenditure**, contributing to further weight gain. **Impact on Energy Expenditure and Food Intake** The hypothalamus integrates signals from leptin and other hormones to regulate two key processes: Food Intake: If leptin signals are functioning correctly, high leptin levels reduce appetite. But with leptin resistance, the brain continues to promote eating even when fat stores are full. Energy Expenditure: Proper leptin signaling increases **thermogenesis** (heat production) and energy burning. In leptin resistance, this process is impaired, reducing the body\'s ability to expend energy, leading to weight gain. **Role of Hypothalamic Inflammation** In obese individuals, fat tissue can also lead to **inflammation** in the brain, particularly in the hypothalamus. This inflammation disrupts normal leptin signaling, exacerbating leptin resistance and further promoting obesity. Wild type = This term is used to describe animals (often mice) that have not been genetically modified and possess a normal, natural genotype. These animals serve as a control group in experiments. Ob/Ob (Obese): This refers to a specific genetic mutation in mice. The Ob/Ob mice are homozygous for a mutation in the **ob gene**, which leads to leptin deficiency. Leptin is a hormone crucial for regulating body weight by inhibiting hunger. Without functional leptin, Ob/Ob mice do not receive signals to stop eating, leading to excessive food intake and severe obesity. [Is leptin the cure? ] Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin (=leptin resistance). NPY = neuropeptide Y Agrp = agouti related peptide - Both stimulate feeding POMC = proopiomelanocortin CART = cocaine and amphetamine regulated transcript - Both are peptides that inhibit feeding **The Hypothalamus and Feeding Regulation**:\ The hypothalamus is a central brain region that integrates signals related to hunger, energy expenditure, and body weight. Leptin binds to receptors in the hypothalamus, particularly in the **arcuate nucleus (ARC)**, which is home to two main types of neurons: **NPY/AgRP Neurons:** These neurons **stimulate feeding** (increase appetite) and are typically active when the body needs energy. **POMC/CART Neurons:** These neurons **suppress feeding** (reduce appetite) and are activated by leptin to promote satiety. **Role of Leptin in the Hypothalamus**:\ **Leptin** normally acts as a signal to reduce hunger. It activates **POMC/CART neurons**, leading to a decrease in food intake, and inhibits **NPY/AgRP neurons**, reducing hunger signals.\ In a healthy system, high leptin levels (due to sufficient body fat) signal the brain that energy stores are adequate, thus suppressing appetite and increasing energy expenditure. **Peptides Involved**:\ **NPY** (Neuropeptide Y): Increases appetite. Leptin **inhibits NPY** to reduce food intake.\ **AgRP** (Agouti-related peptide): Also increases appetite. Leptin **suppresses AgRP** to decrease hunger.\ **POMC** (Pro-opiomelanocortin): Produces alpha-MSH, which decreases appetite. Leptin **activates POMC** to enhance satiety.\ **CART** (Cocaine- and amphetamine-regulated transcript): Works with POMC to reduce hunger. **Why Leptin Isn\'t Always the Cure**:\ In cases of **leptin resistance**, commonly seen in obesity, the brain no longer responds effectively to leptin signals, even if leptin levels are high. This means that even with more leptin, appetite may not decrease as expected, making leptin less effective as a treatment for obesity. [Leptin deficiency] Boy that didn't make leptin and he was overweight. Then they gave him leptin treatment and at 7 he was not overweight anymore. Neuropeptides important in regulation of feeding. Fasting -\> increases NPY neurons. Are activated when you are stimulated to eat. Increases AGRP, decreases POMC -\> stimulates feeding. 1. **Fasting Increases NPY Neuron Activity**: - When you fast, your body detects a decrease in energy availability. - This leads to an increase in the activity of **NPY/AgRP neurons**. - As a result, more **NPY and AgRP** are released. 2. **Effects of NPY and AgRP**: - **NPY** directly stimulates hunger by acting on receptors in the hypothalamus, driving you to eat. - **AgRP** antagonizes MC4R, blocking the appetite-suppressing signals from α-MSH (produced by POMC neurons). - The combined effect of NPY and AgRP is a powerful **stimulation of feeding** and reduction of energy expenditure. 3. **Decrease in POMC Neuron Activity**: - Fasting also results in the **inhibition of POMC neurons**. - This reduces the release of **α-MSH**, lowering the activation of MC4R, which would normally suppress appetite. - The suppression of POMC activity further enhances the drive to eat. **Summary of the Feedback Loop** - **Fasting** → **↑ NPY/AgRP activity** → **↑ AgRP (blocks MC4R)** → **↓ POMC neuron activity** → **↑ hunger and food intake**. - This process ensures that during times of low energy (like fasting), your brain increases the drive to eat to replenish energy stores. What else can activate POMC neurons? Nicotine. Often when people stop smoking, they become hungrier, and that is because nicotine activates POMC neurons. And POMC neurons decreases appetite. MC4R: **Gene**: The MC4R gene encodes the melanocortin 4 receptor. MC4R is highly expressed in the **hypothalamus**, a region of the brain that controls hunger and satiety. MC4R is activated by several peptides derived from the **Proopiomelanocortin (POMC)** precursor, particularly: - **α-MSH (alpha-melanocyte-stimulating hormone)**, which **activates** MC4R. - **Agouti-related peptide (AgRP)**, which **antagonizes or blocks** MC4R. The **MC4R** is a critical receptor in the brain that helps regulate **appetite and energy balance**. It acts as a \"brake\" on food intake when activated by α-MSH from POMC neurons. Conversely, it can be blocked by AgRP during fasting, leading to increased hunger. Disruptions in the MC4R signaling pathway can lead to obesity, making it a significant target for understanding and treating metabolic diseases. MC4R is downstream of AgRP/NPY and POMC neurons in Arcuate nucleus which means that MC4R **acts** after the signal from AgRP/NPY and POMC neurons. MC4R is a receptor and when POMC binds and activates MC4R it suppresses appetite and promotes energy expenditure. AgRP/NY blocks the MC4R receptor and prevents the appetite-suppressing effects of α-MSH. Leading to increasing hunger.  MC4R mutations are associated with obesity. Heterozygous mutations (one copy of the gene is mutated) in MC4R are the most common cause of obesity in humans. Homozygous mutations in MC4R frequency is 0.3% in UK cohort. The melanocortin 4 receptor shows constitutive activity *MC4R and leptin deficiency* If we give leptin treatment the food intake in a normal animal should go down and energy expenditure would increase. If we do this in MC4R -/- (KO) it would be insufficient because the receptor is not there, and the signal will not go further. Leptin deficient animal -- leptin treatment will cause food intake decrease and energy expenditure increase. **-/-**: This indicates that **both copies of the gene are inactivated** or deleted. In genetics, the symbol **\"-\"** means a **non-functional or missing gene copy**. - **+/+** means both copies of the gene are normal (wild-type). - **+/-** means one normal copy and one mutated or knocked-out copy (heterozygous). - **-/-** means both copies are knocked out (homozygous knockout). **KO** stands for **Knockout**, meaning the gene has been deliberately **inactivated or removed** through genetic engineering techniques. *Cause of obesity* Obesity is a polygenic disease, environment influences it. Polygenic obesity is the common variant: modest genetic contribution, hundreds of variants in or near many genes, each variant has a small effect, it's common, low penetrance and the environment is a key determinant. We have a monogenic variant, severe obesity, like leptin (ob -/-) and melanocortin 4 receptor (MC4R -/-). It has a high genetic contribution, single mutation in one gene, large genetic effect, rare, high penetrance and no environmental influence. *Chemogenetic activation of AgRP neurons drives caloric intake.* Chemogenetics is a method that allows scientists to control the activity of specific neurons using engineered receptors and designer drugs. **DREADD** stands for \"Designer Receptors Exclusively Activated by Designer Drugs.\" These are modified receptors that do not naturally occur in the body. They can be inserted into specific neurons (like AgRP neurons) using genetic techniques. DREADD receptors are activated only by specific synthetic compounds (like **CNO** - clozapine-N-oxide) that do not affect normal brain function. This allows researchers to selectively activate or inhibit certain neurons with precision. **How DREADDs Work in AgRP Neurons**: - In the context of the experiment shown on slide 45: - Researchers use DREADD technology to **activate AgRP neurons** in mice. - By administering the designer drug (CNO), they can turn on AgRP neurons at will, regardless of the animal\'s actual energy needs. - When these neurons are activated, the mice **experience increased hunger** and **consume more calories**, even if they are not naturally hungry. - This demonstrates that simply activating these neurons is enough to **drive food intake**, showing how powerful AgRP neurons are in regulating feeding behavior. **Purpose of This Research**: - By using chemogenetics to manipulate AgRP neurons, scientists can better understand the neural mechanisms behind **hunger and obesity**. - It highlights the critical role of AgRP neurons in the brain\'s control of appetite and shows how dysregulation in this system can lead to overeating and weight gain. Optogenetic activation of AgRP neurons drives caloric intake (with light) -- AgRP neurons are activated through light after being genetically modified to express light-sensitive ion channels. Shine light on the receptor will stimulate the activation of the cells. [Reward circuity] **Anticipatory/approach** phase of feeding -- dopamine - 'wanting' of food. Vs. **hedonic aspects** of the consummatory act -- opioids - 'liking' of food. Extracellular dopamine levels in nucleus accumbens increase with substances that are rewarding (cocaine, alcohol, but also sugar). **Nucleus accumbens (NAc)** is a critical brain region within the reward pathway. It\'s part of the **mesolimbic dopamine system**, often referred to as the \"reward center.\" When a person consumes something rewarding (such as drugs, alcohol, or sugar), **dopamine levels** in the nucleus accumbens **increase**. This surge in dopamine reinforces the behavior, making the person more likely to seek out that experience again. **D2 receptor binding** is often used as a marker for dopamine function in the brain. Reduced D2 receptor availability (or binding) in certain areas of the brain has been associated with a greater tendency toward addictive behaviors and a diminished ab