Summary of all lectures of Molecular Principles of Brain Disorders
1. Etiology of mental traits and brain disorders - p 2
2. Etiology of mental traits and brain disorders – paper discussion - p 10
3. Common mechanisms in neurodegeneration - p 14
4. Dementia 1+2 - p 23
5. Synucleinopathies + prion disease and prion like spreading - p 30
6. Therapy 1-3 - p 38
7. Stemcells + 100 + study - p 55
8. Depression part 1tm3 - p 65
9. ADHD - p 78
10. Neurobiology of Antisocial behavior personality disorder - p 86
11. Neurodiversity in ADHD and ASD - p 95
12. Schizophrenia - p 98
13. Bright side of mental illness part 1&2 p - 109
1
,Lecture 1 - Week 1
Etiology of brain disorders
Trait or disorder?
Trait impulsivity => trait that exists on a spectrum
> When high or low? When does it become pathological?
> The line changes, but also the frequency
LOW ----------------------------------------- AVERAGE ----------------------------------
HIGH
- Non-impulsive - Cautious - Average - More impulsive
- Extreme impulsive
- Paralyzed in though
There is a lot of variation in kinds of traits → in etiology want to know: what causes
this variation?
● Variation in genes
● Variation in environmental circumstances that we are exposed to?
● What is the weight of these 2?
● What is the border between normal and abnormal behavior? Who
decides this?
Deciding what is pathological or not is very subjective, which makes it hard to
distinguish pathologies from and within people. This might lead to incorrect
conclusions (we all see a filtered version of reality).
Past/ Old paradigm: tendency to explain disease via ‘nurture’ concept
→ Autism because of distant mother
→ Homosexual orientation because of overly
present mother Only later biological factors
became clearer
2
,Hard reductionism =‘all psychiatric illnesses are best explained solely in terms of
molecular neuroscience’
Etiological models for psychiatric disease need to be pluralistic or multilevel. Break
down dichotomy between nature-nurture, but view brain as in constant interaction
with environment, society and culture via plasticity
Etiology is a complex puzzle of interaction between genes and environment.
Genes:
Most of the evidence for the influence of genes on traits come from twin + adoption
studies: several behavioral traits and psychiatric diseases moderate / high
heritability.
Within these studies we often speak of heritability. From the concordance rates, you
can calculate the variable: heritability.
Heritability = proportion of variance in symptoms that is explained by the variance in
genetic factors (Which means, that if you look at a certain population (dutch
population), and you want to see what is the variety in ADHD => 75% of the
variation in ADHD that is seen in dutch population is due to genes).
Major depression: 40-50%; ASPD: 40-50%; autism, bipolar disorder and
schizophrenia around 80%
Human genome project : Model of single/few risk genes was overly
simplistic. Single abnormal gene is not sufficient to cause mental disorders
So we know that the influence of genes is there (because of twin studies), but it is
hard to find the underlying variance of genes, this is called: ‘missing heritability’.
One of the reasons for missing heritability is that the model is overly simplistic. There
are more than 100 genes that play a role in the color of your eyes alone, let alone
the complexity of a pathology such as depression.
So the Classic theory, which states that: Single abnormal gene > abnormal gene
product > neuronal malfunction > mental illness, is no longer correct!
New paradigm: mental illness is caused by multiple small contributions from
several genes, all interacting with environmental stressors → complex genetics
Complex set of risk factors biases a person towards illness but
does not cause it. Person inherits risk factors, not actual illness.
3
, New models for pathway: ‘genotype to phenotype’:
1. ‘Complex Genetics’ or ‘Diathesis-Stress Model’ (explained in lecture
Etiology)
2. ‘Differential Susceptibly to Environment Hypothesis’ (explained in lecture
‘looking at the bright side of mental illnesses’)
3. ‘Balancing Selection Hypothesis’ (also explained in lecture ‘looking at
the bright side of mental illnesses’)
Stress – diathesis model = you can have a genetic predisposition (= certain gene
variants) that makes you more vulnerable, BUT you will only get a certain trait when
you have environmental stress → so interaction: it increases the probability that you
have a certain disorder/disease
Etiology of psychiatric disorders is moving beyond receptors, enzymes
and other molecules as causes for mental illness → psychiatric symptoms are
increasingly linked to malfunctioning specific brain circuits (brain imaging)
Introduce levels of variables that are in between genotype and phenotypes →
endophenotypes
Instead of only looking into the risk genes, you also look at specific variables and
traits of disorders that are also indirectly linked to genes but are easier to
measure.
Endophenotype approach: link
gene to endophenotype more
precisely measurable than to
disease (Complex disorders are
fragmentized to be studied).
Yo u h a v e t w o t y p e s o f
endophenotypes: 1. Biological
endophenotypes
2. Symptom endophenotypes
4
1. Etiology of mental traits and brain disorders - p 2
2. Etiology of mental traits and brain disorders – paper discussion - p 10
3. Common mechanisms in neurodegeneration - p 14
4. Dementia 1+2 - p 23
5. Synucleinopathies + prion disease and prion like spreading - p 30
6. Therapy 1-3 - p 38
7. Stemcells + 100 + study - p 55
8. Depression part 1tm3 - p 65
9. ADHD - p 78
10. Neurobiology of Antisocial behavior personality disorder - p 86
11. Neurodiversity in ADHD and ASD - p 95
12. Schizophrenia - p 98
13. Bright side of mental illness part 1&2 p - 109
1
,Lecture 1 - Week 1
Etiology of brain disorders
Trait or disorder?
Trait impulsivity => trait that exists on a spectrum
> When high or low? When does it become pathological?
> The line changes, but also the frequency
LOW ----------------------------------------- AVERAGE ----------------------------------
HIGH
- Non-impulsive - Cautious - Average - More impulsive
- Extreme impulsive
- Paralyzed in though
There is a lot of variation in kinds of traits → in etiology want to know: what causes
this variation?
● Variation in genes
● Variation in environmental circumstances that we are exposed to?
● What is the weight of these 2?
● What is the border between normal and abnormal behavior? Who
decides this?
Deciding what is pathological or not is very subjective, which makes it hard to
distinguish pathologies from and within people. This might lead to incorrect
conclusions (we all see a filtered version of reality).
Past/ Old paradigm: tendency to explain disease via ‘nurture’ concept
→ Autism because of distant mother
→ Homosexual orientation because of overly
present mother Only later biological factors
became clearer
2
,Hard reductionism =‘all psychiatric illnesses are best explained solely in terms of
molecular neuroscience’
Etiological models for psychiatric disease need to be pluralistic or multilevel. Break
down dichotomy between nature-nurture, but view brain as in constant interaction
with environment, society and culture via plasticity
Etiology is a complex puzzle of interaction between genes and environment.
Genes:
Most of the evidence for the influence of genes on traits come from twin + adoption
studies: several behavioral traits and psychiatric diseases moderate / high
heritability.
Within these studies we often speak of heritability. From the concordance rates, you
can calculate the variable: heritability.
Heritability = proportion of variance in symptoms that is explained by the variance in
genetic factors (Which means, that if you look at a certain population (dutch
population), and you want to see what is the variety in ADHD => 75% of the
variation in ADHD that is seen in dutch population is due to genes).
Major depression: 40-50%; ASPD: 40-50%; autism, bipolar disorder and
schizophrenia around 80%
Human genome project : Model of single/few risk genes was overly
simplistic. Single abnormal gene is not sufficient to cause mental disorders
So we know that the influence of genes is there (because of twin studies), but it is
hard to find the underlying variance of genes, this is called: ‘missing heritability’.
One of the reasons for missing heritability is that the model is overly simplistic. There
are more than 100 genes that play a role in the color of your eyes alone, let alone
the complexity of a pathology such as depression.
So the Classic theory, which states that: Single abnormal gene > abnormal gene
product > neuronal malfunction > mental illness, is no longer correct!
New paradigm: mental illness is caused by multiple small contributions from
several genes, all interacting with environmental stressors → complex genetics
Complex set of risk factors biases a person towards illness but
does not cause it. Person inherits risk factors, not actual illness.
3
, New models for pathway: ‘genotype to phenotype’:
1. ‘Complex Genetics’ or ‘Diathesis-Stress Model’ (explained in lecture
Etiology)
2. ‘Differential Susceptibly to Environment Hypothesis’ (explained in lecture
‘looking at the bright side of mental illnesses’)
3. ‘Balancing Selection Hypothesis’ (also explained in lecture ‘looking at
the bright side of mental illnesses’)
Stress – diathesis model = you can have a genetic predisposition (= certain gene
variants) that makes you more vulnerable, BUT you will only get a certain trait when
you have environmental stress → so interaction: it increases the probability that you
have a certain disorder/disease
Etiology of psychiatric disorders is moving beyond receptors, enzymes
and other molecules as causes for mental illness → psychiatric symptoms are
increasingly linked to malfunctioning specific brain circuits (brain imaging)
Introduce levels of variables that are in between genotype and phenotypes →
endophenotypes
Instead of only looking into the risk genes, you also look at specific variables and
traits of disorders that are also indirectly linked to genes but are easier to
measure.
Endophenotype approach: link
gene to endophenotype more
precisely measurable than to
disease (Complex disorders are
fragmentized to be studied).
Yo u h a v e t w o t y p e s o f
endophenotypes: 1. Biological
endophenotypes
2. Symptom endophenotypes
4
