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Molecular Principles Of Brain Disorders samenvatting
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Voorbeeld van de inhoud
HC ETIOLOGY OF MENTAL TRAIT AND DISORDERDPart 1 etiology
Traits and disorder:
- Impulsivity, mood, (anti) social behavior, stress-sensitivity, resilience and vulnerability are
behavioral traits
- Each trait exists along a spectrum
- Impulsivity (extremely thoughtful, difficulties decision taking – extremely impulsive)
- Border between normal and abnormal behavior?
- A variation or a disorder?
- Other traits: IQ, extraversion, blood pressure
- Disorders: diabetes, obesity, autism, depression, schizophrenia traits become pathological
- HOW do traits and disorders arise in general?
Which factors can contribute to traits/(mental) characteristics and brain disorders?
- Genes -> nature
- Environmental factors -> nurture
Nature and nurture discussion:
- Past tendency to explain disease via nurture concepts
- Autism: refrigerator mother
- Homosexual orientation: overly present mother
- Later: role biological factors more clear (nature)
Etiology:
- Classical nature-nurture discussion -> outdated:
Hard reductionism -> all psychiatric illness is best explained solely in terms of
molecular neuroscience
Etiological models for psychiatric disease need to be pluralistic or multilevel
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
Most brain disorders complex, multifactorial disorders
Both genetic and environment factors involved in etiology
Often -> complex interactions and causal loops
Part 2 – genes and psychiatry
Genes:
- From twin + adaption 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. The part of the variation in symptoms you see across population that can be
explained by the variation these people have in their genes -> the higher the number the
higher the heritability. Heritability is a statistic used in the fields of breeding and genetics
that estimates the degree of variation in a phenotypic trait in a population that is due to
genetic variation between individuals in that population.
- Major depression 40-50%
- ADHD 75%
- Autism, bipolar disorder and schizophrenia 80%
, - If you look at ADHD and you look at the whole population of people with ADHD -> variation
in the symptoms you have -> what is the cause of their variation? -> is the variation due to
their genes or is the variation due to a variation in environmental risk factors. In the case of
ADHD a 75% heritability means that for the whole ADHD population 75% of the variation in
symptoms you can explain by a variation in their genes. 25% of the variation in their
symptoms among the whole ADHD population is due to the variation in environmental
factors.
In post human genome project era:
- Expectation: easy to find risk gene variant
- Contrary: very difficult
- Twin studies -> compare concordance of certain trait in monozygotic twins compared to
dizygotic twins. Monozygotic twins share 100% same genes, dizygotic twins have around 50%
of their DNA in common, but they spend the same time in the same womb so they have
environmental factors in common. By comparing the concordance rate of monozygotic twins
with dizygotic twins, if its higher in monozygotic twins the heritability will be higher.
Heritability is calculated through twin studies.
- Missing heritability
- But we know genes play a substantial role
- Model of single/ few risk genes -> overly simplistic paradigm -> need new models to explain
these phenomena.
Classic theory:
- Single abnormal gene -> abnormal gene product -> neural malfunction -> mental illness
But we see that
- Single abnormal gene is not sufficient to cause mental disorders
What is pathway from gene to mental illness??
New explanations, new hypothesis, new models for pathway genotype to phenotype:
1. Complex genetics or diathesis-risk model (etiology lecture)
2. Differential susceptibility to environment hypothesis (neurobiology of resilience)
3. Balancing selection hypothesis (mental illness & creativity)
1|
- New hypotheses and new models are complex
- New ways of doing research and unravel these pathways from genotype to phenotype:
endophenotype approach
Stress-diathesis model (diathesis -> 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. Too many
Complex genetics/ stress -diathesis model
Complex set of risk factors that bias person toward illness but do not cause it
(inherits risk not disease). Even if you have a lot of risk factors there is still a chance
that you do not develop the disease.
Reaching tipping point: high probability developing disorder
Concept also applies to hypertension, obesity, diabetes…..
Part 3 – endophenotype approach
,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 much more
complex
- Solution: important intermediaries (variables)
between gene (genotype) and disease/behavior
(phenotype) -> extra set of variables to make the
pathway more easy to unravel
- Endophenotypes are variables in between the
genotype and the phenotype
- They need to be measurable, inheritable and
closely linked to disease
- More precisely measurable than the illness
- Two types:
1. Biological endophenotypes
2. Symptom/system endophenotypes
Biological endophenotypes -> measurable biological phenomena
- Electrophysiological response to startle -> schizophrenia
- Neuroimaging response to information processing
- Activation of certain brain circuit -> hyper active amygdala in anxiety and depression
Symptom/system endophenotypes -> single symptoms associated with mental illness (check the
boxes for certain symptoms -> and then you get the label)
- Anhedonia -> depression and schizophrenia
- Insomnia
- Executive dysfunction -> malfunction in prefrontal cortex
- Hallucinations
- Poor fear conditioning
Instead of looking at people with a certain disorder, you look at people with a combination of
symptoms. You make fragmentations in the difficult pathways to make it easier.
- Gene -> molecules -> circuit -> information processing (biological phenotype) -> single
symptom (system endophenotype) -> full syndrome of mental disorder
- Closed to gene on pathway -> more readily linked to gene: link gene to endophenotype
easier than to disease
- Genes only loosely linked to psychiatric disorders, therefor hard to identify
Psychiatry and brain circuits:
- Etiology of psychiatric disorders is moving beyond
receptors, enzymes and other molecules as causes for
mental illness
- New paradigm: psychiatric symptoms are increasingly
linked to malfunctioning specific brain circuits
(connections between neurons) -> you can break a
circuit in many different ways but the result will stay
the same Circuit based psychiatry
- Genes + environmental risk factors conspire to
produce inefficient information processing in neuronal
circuitry
- Brain imaging -> focus on brain circuits
, Why are subtle molecular abnormalities not more penetrant at behavioral level?
- Multiple genes complementary/ redundant effects healthy compensatory backup systems ->
risk genes are not necessary sufficient to cause mental illness
- COMBINATION WITH ENVIRONMENTAL RISK FACTRS
(STRESS, LIFE EVENTS, BIOLOGICAL STRESSORS SUCH AS
VIRUSES)
Part 4 – social-ecological framework & environmental risk factors
Social-ecological framework:
- 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 -> Also genetic factors are individual factors
Relationship
Cultural/environmental factors
Environmental factors:
- Pre/peri natal risk factors:
Maternal stress during pregnancy
Maternal nutritional deficiency
Maternal use of tobacco / alcohol / drugs / medication
Birth complications
Perinatal nutritional deficiency
Maternal separation -> relationship
- Abuse: sexual, physical or emotional
- Neglect relationships
- Poor parental care
- Biological factors:
Infections
Toxins
Brain trauma
Drug use
- Stressful life events
- Low SES
- Poverty
- Community violence
- Mental health care and health care policy
Access to care
Stigmatization of mental health problems
- Minority group position
- Cultural factors
- Religious factors both beneficial or harming
Part 5 – stress system
Consisting of a fast acting and a slow acting pathway.
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