Molecular Principles of Brain Disorders
Lecture 1: Etiology of Brain Disorders
Traits exist along a spectrum. Genes and environment contribute to the outcome of these characteristics.
Examples are impulsivity, mood, stress-sensitivity, etc. In the past people had the tendency to look via the
nurture concept: homosexuality comes from an overly present mother for instance. The nature-nurture
discussion is on the other hand lead by hard reductionists, that said that all psychiatric illnesses are explained
by solely molecular neuroscience. However, etiological models for diseases of the brain need to be pluralistic,
multilevel: with biological, psychosocial, sociocultural and economic perspectives. Most disorder are
multifactorial. They often have complex interactions and causal loops.
Genes
In twinstudies they found several behavioural traits and psychiatric disorders and their heritability. For
instance: MDD 40-50% and schizophrenia 80%.
Heritability: Heritability: proportion of variance in symptoms that is explained by the variance
in genetic factors
With human genome project, people thought I’d be easy to identify those risk genes, however this turned out
to be very difficult. They could only find about 3% of risk genes, so there was major ‘missing heritability’. The
model of single risk genes is overly simple. With the use of other hypotheses and models, they wanted to find
genotype to phenotype:
- Complex genetics (Diasthesis-Risk model)
- Differential susceptibility to environment hypothesis
- Balancing selection hypothesis
These models are more complex and need an endophenotype approach.
Stress-diathesis model (diathesis=risk): preposition + environmental stress → disease
This is complex genetics, small contributions from several genes are all interacting with environmental
stressors. This biases the person towards a condition, but does not cause it. The risk is thus inherited and not
the disease. When tipping point reached: high probability of developing condition. This does not only apply to
mental conditions obviously. The endophenotype approach is used, which is much more complex!
Intermediaries are used between gene and disease. The closer to the gene on the pathway, the more readily
linked to the gene. There are to types of endophenotypes:
- Biological endophenotypes
o Measurable biological phenomena, for instance: activation of certain brain circuits.
- Symptom/system endophenotypes
o Single symptoms associated with disease, for instance: anhedonia and hallucinations
Gene > molecule > circuits > information processing > single symptoms > full disorder/condition.
So etiology of psychiatric conditions moves beyond receptors and enzymes and that. Symptoms are
increasingly linked to malfunctioning of specific brain circuits.
Why are subtle molecular abnormalities not more penetrant at behavioural level: genes have a back up system,
so a lot of faults are balances out. Risk genes thus, are not necessary sufficient to cause the disorder.
Socio-ecological framework
It’s a dynamic interplay of risk and protective factors. These factors occure along a social ecology continuum.
Can be individual, relationship and environmental factors. Genetic factors are by the way individual factors.
- Environmental factors could literally be anything in life:
o pre-/peri natal risk factors: maternal stress, nutritional deficiency, use of alcohol, tobacco,
drugs, seperation
o birth complications, abuse, neglect/poor parental care, toxins, brain trauma
o Low SES, poverty, community violence
o Health care + access to it
o Minority group position, cultural factors, religious factors
,Environmental factors exert their influence by the stress system and
epigenetics.
- Stress system: because of stress the hormone cortisol is
released. This hormone is important in disease response. It binds
the Glucocorticoid Receptor (GR) in the body. GR acts as a
transcription factors and can alter gene expression. GR is also
found in brain areas: hypoth alamus > hypophysis +
hippocampus: negative feedback loop, causses a shu t down of
CRF release.
A sustained high level of cortisol is harmful and causes hypertension,
immunosuppression, structural effects on amygdala and hippocampus
and increases chance of psychopathology. Early life stress causes a life long overactive HPA-axis. There
is less GR, which is less of a negative feedback system to shut down the stress system.
Epigenetics
Life experiences change a persons mind by coating the DNA to ease or block access to DNA. This is
environmental programming of gene expression. Maternal care variations affect HPA-axis responses to stress in
their off spring, mechanism is unknown however.
Lecture 2: ADHD
Inattention, hyperactivity and impulsivity are traits related to ADHD. 80% of ADHD patients is a boy. 2-5% are
children aged 6-16. Symptoms persist into adulthood in about 30-50% cases. Neuroimaging studies have shown
various impaired brain structures in people with ADHD. However, many studies were also underpowered, so
not very reliable:
- Prefrontal cortex: less inhibitory control, thus more impulsive
- Cerebellum & caudate nucleus: motor hyperactivity
- Corpus callosum: less communication hemispheres
The largest study to date of brain volume differences between
participants with and without ADHD consisted of 23 cohort studies and a
total number of 3242 participants. They identified smaller volumes in
amygdala, accumbens and hippocampus with ADHD than in healthy
controls. It was a replication of earlier findings for reduced caudate and
putamen volumes. The largest effect was found in the amygdala. This
sounds similar to problems with emotional regulation in people with
ADHD. These problems are not yet included in DSM criteria.
Good to know: volume differences were clustered in children and at
group level, there were no differences reported in adults.
The most pronounced effects were found in childhood, together with delayed peaks of subcortical volume
maturation gives us a model of ADHD as a disorder of brain maturation delay.
In the article itself:
- Patients with ADHD have altered brains → ADHD is a disorder of the brain
- They want to reduce stigma that ADHD is just a label for difficult children and caused by
incompetent parenting
- Label ADHD as a brain disorder!
Many scientists were critical: these were small effects, it was only group level, it was heterogeneous and
stigmatizing.
Writers said then, that there were no claims about causality.
,Genes
Heritability is 75%. Precise causal genes can’t easily be found in brain conditions. Genome-wide association
study was largely inconclusive. They found weak associations with DAT gene and DRD4. These genes only
account for about 3% 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 genetics of ADHD.
Non genetic factors
A combination of these factors with genes probably
cause ADHD. A smoking mother is not only for ADHD a
risk factor, but for somewhat every other disease, so
keep that in mind. Severe early deprivation is a likely
causal risk factor!
Treatments
The disease has dysfunctions of the dopamine NT
system (hypodopaminergic condition).
- Methylphenidate and amphetamine: block reuptake of dopamine (DAT receptors) and thus
increase the DA concentration.
This is however an oversimplification.
Multimodel Treatment Study of Children with ADHD was done in the USA to study the effectiveness of the
treatments. This is the largest longitudinal study in child psychiatry. It concluded 579 children aged 7-9 and
were put in four random treatment groups:
- Standard community care: often prescribed medication, treatment by community providers.
- Intensive behavioral therapy without medication (BT)
- Intensive carefully tailored medical treatment (MED)
- Combination medication with behavioral therapy (COMB)
Findings: all four groups showed sizable reductions in symptoms over time.
- Most ADHD symptoms: COMB and MED: significantly greater improvement than Intensive BT
and community care
- Study medication strategies were superior to community care treatments, despite the fact
that 2/3 of community-treated subjects received medication during study period.
- COMB and MED management treatments: no significant difference on any direct
comparisons for core ADHD symptoms.
- But: COMB proved superior for non-ADHD symptoms (according DSM) and positive
functioning outcomes, such as aggressiveness, internalizing symptoms, teacher-rated social
skills etc).
Follow-up 8 years later: symptom improvement largely maintained after treatment. In nearly every analysis,
the four groups did not differ significantly on repeated measures/newly analyzed variables . So, intensive
treatments did not have long-term benefits.
Conclusion + recommendation: temporarily stop medication, determine whether benefits are lost.
Loss of benefits suggests that the medication is still useful and you should keep doing it.
Study (Nakao et all.): does ADHD medication have any effect on brain abnormalities. They looked structurally in
the grey matter volume using MRI and functionally, through inhibition and attention tasks (fMRI).
- Use of stimulant medication may be associated with normalization of structural
abnormalities in ADHD.
o But: advancing age is also associated with normalization of structural abnormalities
in ADHD.
- But: longitudinal studies are needed.
, Dutch mega-analysis could not replicate (Hoogman et all.):
- Psychostimulant medication has no influence on brain area volumes
- Caution in interpretation: design not optimal to test medication effects > non-randomised
cross-sectional design
- Long term damage not seen
Study (hart et all.):
- fMRI in attention tasks, conclusion: networks work less well in ADHD compared to non
ADHD, so functional differences
- Use of stimulant medication may be associated with more normal activation in caudate
nucleus during attention task
- But: Advancing age also associated with normalization of functional abnormalities in ADHD.
o More longitudal studies needed.
Medication doesn’t cause long term brain damage. Any other side effects? Well, the mechanism of action
methylphenidate resembles that of cocaine. Amphetamine is also used as Speed. Are there because of this
negative consequences of stimulants, such as abuse/dependence?
Study in 2003: stimulant therapy in childhood associated with reduction to the risk of drug and alcohol abuse
later on. This is an old article and has had many replication studies.
- No replications found: no evidence that stimulant treatment increases or decreases the risk
for use disorders in people with ADHD reaching young adulthood.
Some studies do find beneficial effects of stimulant medication, but these are preliminary results, ‘open label’
studies. Good to keep in mind: ADHD as a condition itself increases probability of substance use disorders later
in life.
The effects on growth as a result of stimulant medication were also studied, and there was no evidence of
growth rebound.
Neurodiversity
As we all know, our traits lay on a spectrum. How do we view ADHD, autism etc.: Disorder – diversity? At the
moment we use DSM-V to classify and diagnose brain disorders. This is categorical: you either have a
psychiatric disorder or you don’t . Many disorders however, are better conceptualized as dimensional and lay
on a spectrum. Autism Spectrum Disorder (ASD) is now approached in that way. High functioning autistic
people prefer the concept of neurodiversity.
ADHD and ASD are generally described in a negative way: overactive, easily distracted etc. or: impaired social
relationships, strange behaviour etc. Emphasis could also be placed on more positive aspects of conditions:
Spontaneous, vital, high-energy etc. and: strong persistent interest, attention to detail, unusual memory etc.
Growing interest in researching high functioning autistics. They outperform neurologically typical children and
adults in a wide range of perception tasks:
- Spotting pattern in distracting environment
- Auditory tasks
- Detecting visual structures and mentally manipulating complex 3D-shapes
- Raven’s matrices
- Simultaneously process large pieces of perceptual information, such as large data sets.
Neurodiversity in practive: be aware of your mental condition, strong points, pitfalls, adjust life and
surroundings to your unique qualities: niche construction.
Niche construction for ADHD: choose job in nature, be physically engaged, handling emergencies etc.
Niche construction for ASD: choose job in IT, high concentration, solitary work etc.
The pitfall of neurodiversity is the romanticization of psychiatric conditions. There are almost no advantages for
conditions like depression and schizophrenia!
Lecture 1: Etiology of Brain Disorders
Traits exist along a spectrum. Genes and environment contribute to the outcome of these characteristics.
Examples are impulsivity, mood, stress-sensitivity, etc. In the past people had the tendency to look via the
nurture concept: homosexuality comes from an overly present mother for instance. The nature-nurture
discussion is on the other hand lead by hard reductionists, that said that all psychiatric illnesses are explained
by solely molecular neuroscience. However, etiological models for diseases of the brain need to be pluralistic,
multilevel: with biological, psychosocial, sociocultural and economic perspectives. Most disorder are
multifactorial. They often have complex interactions and causal loops.
Genes
In twinstudies they found several behavioural traits and psychiatric disorders and their heritability. For
instance: MDD 40-50% and schizophrenia 80%.
Heritability: Heritability: proportion of variance in symptoms that is explained by the variance
in genetic factors
With human genome project, people thought I’d be easy to identify those risk genes, however this turned out
to be very difficult. They could only find about 3% of risk genes, so there was major ‘missing heritability’. The
model of single risk genes is overly simple. With the use of other hypotheses and models, they wanted to find
genotype to phenotype:
- Complex genetics (Diasthesis-Risk model)
- Differential susceptibility to environment hypothesis
- Balancing selection hypothesis
These models are more complex and need an endophenotype approach.
Stress-diathesis model (diathesis=risk): preposition + environmental stress → disease
This is complex genetics, small contributions from several genes are all interacting with environmental
stressors. This biases the person towards a condition, but does not cause it. The risk is thus inherited and not
the disease. When tipping point reached: high probability of developing condition. This does not only apply to
mental conditions obviously. The endophenotype approach is used, which is much more complex!
Intermediaries are used between gene and disease. The closer to the gene on the pathway, the more readily
linked to the gene. There are to types of endophenotypes:
- Biological endophenotypes
o Measurable biological phenomena, for instance: activation of certain brain circuits.
- Symptom/system endophenotypes
o Single symptoms associated with disease, for instance: anhedonia and hallucinations
Gene > molecule > circuits > information processing > single symptoms > full disorder/condition.
So etiology of psychiatric conditions moves beyond receptors and enzymes and that. Symptoms are
increasingly linked to malfunctioning of specific brain circuits.
Why are subtle molecular abnormalities not more penetrant at behavioural level: genes have a back up system,
so a lot of faults are balances out. Risk genes thus, are not necessary sufficient to cause the disorder.
Socio-ecological framework
It’s a dynamic interplay of risk and protective factors. These factors occure along a social ecology continuum.
Can be individual, relationship and environmental factors. Genetic factors are by the way individual factors.
- Environmental factors could literally be anything in life:
o pre-/peri natal risk factors: maternal stress, nutritional deficiency, use of alcohol, tobacco,
drugs, seperation
o birth complications, abuse, neglect/poor parental care, toxins, brain trauma
o Low SES, poverty, community violence
o Health care + access to it
o Minority group position, cultural factors, religious factors
,Environmental factors exert their influence by the stress system and
epigenetics.
- Stress system: because of stress the hormone cortisol is
released. This hormone is important in disease response. It binds
the Glucocorticoid Receptor (GR) in the body. GR acts as a
transcription factors and can alter gene expression. GR is also
found in brain areas: hypoth alamus > hypophysis +
hippocampus: negative feedback loop, causses a shu t down of
CRF release.
A sustained high level of cortisol is harmful and causes hypertension,
immunosuppression, structural effects on amygdala and hippocampus
and increases chance of psychopathology. Early life stress causes a life long overactive HPA-axis. There
is less GR, which is less of a negative feedback system to shut down the stress system.
Epigenetics
Life experiences change a persons mind by coating the DNA to ease or block access to DNA. This is
environmental programming of gene expression. Maternal care variations affect HPA-axis responses to stress in
their off spring, mechanism is unknown however.
Lecture 2: ADHD
Inattention, hyperactivity and impulsivity are traits related to ADHD. 80% of ADHD patients is a boy. 2-5% are
children aged 6-16. Symptoms persist into adulthood in about 30-50% cases. Neuroimaging studies have shown
various impaired brain structures in people with ADHD. However, many studies were also underpowered, so
not very reliable:
- Prefrontal cortex: less inhibitory control, thus more impulsive
- Cerebellum & caudate nucleus: motor hyperactivity
- Corpus callosum: less communication hemispheres
The largest study to date of brain volume differences between
participants with and without ADHD consisted of 23 cohort studies and a
total number of 3242 participants. They identified smaller volumes in
amygdala, accumbens and hippocampus with ADHD than in healthy
controls. It was a replication of earlier findings for reduced caudate and
putamen volumes. The largest effect was found in the amygdala. This
sounds similar to problems with emotional regulation in people with
ADHD. These problems are not yet included in DSM criteria.
Good to know: volume differences were clustered in children and at
group level, there were no differences reported in adults.
The most pronounced effects were found in childhood, together with delayed peaks of subcortical volume
maturation gives us a model of ADHD as a disorder of brain maturation delay.
In the article itself:
- Patients with ADHD have altered brains → ADHD is a disorder of the brain
- They want to reduce stigma that ADHD is just a label for difficult children and caused by
incompetent parenting
- Label ADHD as a brain disorder!
Many scientists were critical: these were small effects, it was only group level, it was heterogeneous and
stigmatizing.
Writers said then, that there were no claims about causality.
,Genes
Heritability is 75%. Precise causal genes can’t easily be found in brain conditions. Genome-wide association
study was largely inconclusive. They found weak associations with DAT gene and DRD4. These genes only
account for about 3% 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 genetics of ADHD.
Non genetic factors
A combination of these factors with genes probably
cause ADHD. A smoking mother is not only for ADHD a
risk factor, but for somewhat every other disease, so
keep that in mind. Severe early deprivation is a likely
causal risk factor!
Treatments
The disease has dysfunctions of the dopamine NT
system (hypodopaminergic condition).
- Methylphenidate and amphetamine: block reuptake of dopamine (DAT receptors) and thus
increase the DA concentration.
This is however an oversimplification.
Multimodel Treatment Study of Children with ADHD was done in the USA to study the effectiveness of the
treatments. This is the largest longitudinal study in child psychiatry. It concluded 579 children aged 7-9 and
were put in four random treatment groups:
- Standard community care: often prescribed medication, treatment by community providers.
- Intensive behavioral therapy without medication (BT)
- Intensive carefully tailored medical treatment (MED)
- Combination medication with behavioral therapy (COMB)
Findings: all four groups showed sizable reductions in symptoms over time.
- Most ADHD symptoms: COMB and MED: significantly greater improvement than Intensive BT
and community care
- Study medication strategies were superior to community care treatments, despite the fact
that 2/3 of community-treated subjects received medication during study period.
- COMB and MED management treatments: no significant difference on any direct
comparisons for core ADHD symptoms.
- But: COMB proved superior for non-ADHD symptoms (according DSM) and positive
functioning outcomes, such as aggressiveness, internalizing symptoms, teacher-rated social
skills etc).
Follow-up 8 years later: symptom improvement largely maintained after treatment. In nearly every analysis,
the four groups did not differ significantly on repeated measures/newly analyzed variables . So, intensive
treatments did not have long-term benefits.
Conclusion + recommendation: temporarily stop medication, determine whether benefits are lost.
Loss of benefits suggests that the medication is still useful and you should keep doing it.
Study (Nakao et all.): does ADHD medication have any effect on brain abnormalities. They looked structurally in
the grey matter volume using MRI and functionally, through inhibition and attention tasks (fMRI).
- Use of stimulant medication may be associated with normalization of structural
abnormalities in ADHD.
o But: advancing age is also associated with normalization of structural abnormalities
in ADHD.
- But: longitudinal studies are needed.
, Dutch mega-analysis could not replicate (Hoogman et all.):
- Psychostimulant medication has no influence on brain area volumes
- Caution in interpretation: design not optimal to test medication effects > non-randomised
cross-sectional design
- Long term damage not seen
Study (hart et all.):
- fMRI in attention tasks, conclusion: networks work less well in ADHD compared to non
ADHD, so functional differences
- Use of stimulant medication may be associated with more normal activation in caudate
nucleus during attention task
- But: Advancing age also associated with normalization of functional abnormalities in ADHD.
o More longitudal studies needed.
Medication doesn’t cause long term brain damage. Any other side effects? Well, the mechanism of action
methylphenidate resembles that of cocaine. Amphetamine is also used as Speed. Are there because of this
negative consequences of stimulants, such as abuse/dependence?
Study in 2003: stimulant therapy in childhood associated with reduction to the risk of drug and alcohol abuse
later on. This is an old article and has had many replication studies.
- No replications found: no evidence that stimulant treatment increases or decreases the risk
for use disorders in people with ADHD reaching young adulthood.
Some studies do find beneficial effects of stimulant medication, but these are preliminary results, ‘open label’
studies. Good to keep in mind: ADHD as a condition itself increases probability of substance use disorders later
in life.
The effects on growth as a result of stimulant medication were also studied, and there was no evidence of
growth rebound.
Neurodiversity
As we all know, our traits lay on a spectrum. How do we view ADHD, autism etc.: Disorder – diversity? At the
moment we use DSM-V to classify and diagnose brain disorders. This is categorical: you either have a
psychiatric disorder or you don’t . Many disorders however, are better conceptualized as dimensional and lay
on a spectrum. Autism Spectrum Disorder (ASD) is now approached in that way. High functioning autistic
people prefer the concept of neurodiversity.
ADHD and ASD are generally described in a negative way: overactive, easily distracted etc. or: impaired social
relationships, strange behaviour etc. Emphasis could also be placed on more positive aspects of conditions:
Spontaneous, vital, high-energy etc. and: strong persistent interest, attention to detail, unusual memory etc.
Growing interest in researching high functioning autistics. They outperform neurologically typical children and
adults in a wide range of perception tasks:
- Spotting pattern in distracting environment
- Auditory tasks
- Detecting visual structures and mentally manipulating complex 3D-shapes
- Raven’s matrices
- Simultaneously process large pieces of perceptual information, such as large data sets.
Neurodiversity in practive: be aware of your mental condition, strong points, pitfalls, adjust life and
surroundings to your unique qualities: niche construction.
Niche construction for ADHD: choose job in nature, be physically engaged, handling emergencies etc.
Niche construction for ASD: choose job in IT, high concentration, solitary work etc.
The pitfall of neurodiversity is the romanticization of psychiatric conditions. There are almost no advantages for
conditions like depression and schizophrenia!
