Lecture 1: Brain imaging
Name imaging modalities
Describe the technique behind it
Describe neurological …
Why neuroimaging > clinic (diagnosis/prognosis) and research (improve diagnostics, prediction,
understand biological processes.
How to visualize the brain
1. Structural brain imaging
CT doesn’t give anatomical details of the brain. MRI will allow to see difference between tissues
of the brain.
MRI: Big magnet. Have an antenna (receptor, located above the head of the patient) that
receives signals from the brain, but also sends the signal to the brain. The magnet doesn’t
change. Sometimes difficult to apply due to magnetic force.
- Positives > Non-invasive, non-ionizing radiation, good resolution for different tissue (allows
good discrimination).
- Negatives > Quite time-consuming, contradictions to do with metals in patients (e.g. pace
makers), noise, have to be very specific with what you want to see/how long/etc.
NMR = MRI, less scary name for patients. Antenna sends radiofrequency signals to the brain and
some are released from the brain so you can capture them. Look at the protons in hydrogen
parts (water) of the body. Protons are pointing in random directions normally. When enter MRI,
the magnet will force all the protons to point parallel to the magnet of the machine (no signal
yet). The antenna sends radio pulse towards the brain. This will change the direction of the
protons. When no signal anymore, the proton turns back to original position. That change
releases a signal that is sensed by the antenna. The protons not reacting the same (different
tissues) will not give the same signal (e.g. longer time), which allows to see different parts of the
brain. In research now 0.1 mm resolution.
T1 weighted image gives good contrast between cortex and white matter. Contrast between
fat and water (hyposignal). Good to capture anatomy of the brain. E.g. shows main part of
the tumor (see pic). Can see a bit of edema but cant see the borders very well.
T2 weighted image good at showing us the water. Water now gives hypersignal (very high
signal). Useful to detect pathologies (e.g. tumors because most of them are full of water).
Shows edema very well, but see less brain metastasis (see pic).
Often use combination of sequences to get information on different parts.
FLAIR: fluid-attenuated inversion recovery. Take T2 and reverse the signal coming from the
water. CSF is suppressed. Might be easier to see damaged areas. Want to see damaged areas
where most water is present. Suppresses signal from CSF so you can see the border of the
damage more clearly. Can differ between CSF and lesion. Improvement in ventricle part.
Double inversion recovery: suppress both CSF and white matter signal. To see better contrast
between grey and white matter. Basically get only the grey matter. Lesions will be seen as
hypersignals. Can see what is going on in the cortex.
, DWI (diffusion weigthed imaging): mostly look at white matter (is where lot of diseases have
alterations). Water moves freely in unrestricted fields = isotropic. When water is constrained,
it moves differently = anisotropic. Axons restrain the movement of the water. Detect the way
of the water moving, but indirectly shows the direction of the axons. Can also detect the
amount of movement. If e.g. damaged axon, water moves more freely (more diffusion). Can
tell with the imaging. Can make reconstructions based on mathematical models (because you
don’t directly measure the axons, cant count them with MRI).
Tractography: look at connection and fibers of specific regions.
Ischemic stroke
CT scan often used first. MRI gives bit more information (e.g. where the stroke emerged and
where the edema around it is). MRA (angiography) can detect exactly the position of the
blood cloth (allows e.g. surgeon to intervene).
Imaging in research
Qualitative (pathology)
Quantity (structural connectivity)
2. Functional brain imaging
look at what is going on with metabolism of the brain.
PET: inject radioactive isotope into the body. Need to know exactly what you want to measure.
Different tracers depending on need of clinician. Get gamma signals out of the body that are
detected by a specific camera that is going to reconstruct the brain. Often coupled to CT or MRI
(most often CT) to get the anatomy coupled to the metabolism.
MRS (magnetic resonance spectroscopy): done in MRI scanner. Gives a spectrum of different
metabolites that are detected. No ionizing radiation. Bad for spatial resolution (cant see very
small regions).
fMRI: good at knowing how brain is functioning. Shows functional connectivity. Like DWI, it is an
indirect measurement. Look at blood flow around neurons. Diamagnetic (doesn’t create
magnetic field) when oxygenated and when deoxygenated it is paramagnetic (creates magnetic
field). Gives different signals (called BOLD, slight delay in receiving signal). Look at ratio
oxygenated vs deoxygenated blood. Stimulus is applied > increase neuronal activity > demand of
oxygen > increased blood flow > blood more oxygenated > great imbalance between oxygenated
and deoxygenated > signal is measured. Steps are quite fast, but need to go through them first to
be able to measure something. Signal that is obtained is very low. To have better signal, you need
to do it a lot of times and average it. Therefore, we have block design (tasked-based fMRI). Ask a
patient to do certain tasks and scan what regions are active. Alternate tasks a lot of times.
Negative: weak ability to determine the time course of a response. E.g. patient with MS needs
more signal to retrieve same information as a healthy control, cognitive impaired people cant
reach it. Resting state fMRI looks at activity of brain when you are doing nothing. Can recreate a
lot of networks. Can give idea of how brain functions without needing a specific task. Task based
you are restrained with 1 task. Get an idea of what is going on but only for that task. With resting
state, you capture how the brain functions in general.
MEG (magento…): MEG measures the dendritic activity by measuring magnetic fields. EEG
measures electric fields in axons and dendrites. MEG is ‘better’ because > not influenced by
scalp, takes less time, better signal. D3ivide the signals of raw MEG into different bands with their
own traits. MEG has higher temporal resolution. It is a direct measure of neuronal activity. Poo
spatial resolution, difficult to look at deep brain structures.
,Lecture 2a: Preclinical models of drug addiction
Drugs alter behavior and is used to induce strong emotions. Short circuit into the brains reward
system.
Addiction as psychiatric disorder
Initial use is voluntary. Addiction is a chronic, relapsing brain disease. Changes the brain (PET scan).
Define clinical term is substance used disorder (SUD). Diagnosis has evolved from pharmacological
to psychological related symptoms (change in behavior that are related to taking drugs).
Diagnostic and statistical manual of mental disorders is a ‘bible’ in the US used to diagnose
psychiatric disorders.
Multiple levels of SUD. Changes treatment plan.
Different drugs have different risk levels of addiction. E.g. tobacco (31.9% of people using it will
become addicted) has quite a high risk, whereas cannabis has a lot less of becoming addicted.
Validity criteria for animal models for human disorders (always have some limitations (e.g. ethics))
Construct validity
What changes in human is same as what changes in model. Short exposure to a cue can
activate the brain of someone in abstinence.
PET scan shows higher signal in dopamine receptors when exposed to cocaine environment
in both humans and mice (memory formation is comparable).
Face validity
Model mimics the human disorder. All animals self-administer drug when having the chance
(see chimpanzee example).
Relapse
Long-term relapse rates are high. During abstinence, triggers of relapse are drug (laps
causes relapse), stress (social/physical harm), cues (e.g. advertising). See the same
thing in models (face validity).
Predictive validity
Effect in models should also translate to humans. Most important, but no successful
pharmacotherapies for addiction. Much work to do.
Addiction cycle
Non-problematic/recreational drug use > escalation of drug use (take more than anticipated) >
compulsive/problematic use (keep using it despite the harm it is causing us) > abstinence (stop
because of the harm it is causing) > relapse
Using the mouse model
Group of rats suppresses their alcohol intake after 3 days of punishment (shock). Another groups
doesn’t. different suppression ratio.
Are we actually modeling drug addiction in rodents
Choice procedure > between cocaine and sugar. Animals can only choose 1 lever. Found that the
majority of rats chose sugar over cocaine. Also see the difference in humans (some individuals that
will chose the drug as reward). Question is what defines the difference between the group choosing
drugs and the group choosing the other option.
Drug use often in social context. Social-based voluntary abstinence > instead of giving rat drugs, give
them another rat. Can choose between getting drugs and hanging out with friend. 100% chose the
other rat.
, Lecture 2b: ADHD
Response inhibition is the ability to inhibit your response. People suffering from ADHD perform
worse with this task. Will be more likely to press the red button.
Motivational pathway (reward systems of the brain) also play an important role in the causes of
ADHD. This and the response inhibition theory are thought to be the main causes.
What is ADHD
Persistent, pervasive, extremely hyperactive, impulsive and inattentive.
Validity of diagnosis still under discussion. DSM-V criteria help to diagnose. Important difference
between normal (everyone has the symptoms from time to time) and ADHD is duration and how it
affects your life.
ADHD rarely comes alone. Often accompanied by other diseases (e.g. ODD/CD, depression, anxiety).
Diagnosis
No strict objective criteria. Often by multiple informants (parents, teachers, etc).
ADHD disappearing might have to do with the late maturation of the frontal cortex.
Causes
Genetic risk factors
ADHD clusters within families. 75-80% hereditary. Multiple genes contribute, but no clear
model yet.
Polymorphisms
Dopamine receptors have been linked with ADHD. PET study showed binding affinity for
dopamine transporter is much higher in normal people than ADHD patients because of
functional changes in the activity in the brain of ADHD patients.
Structural differences
ADHD and controls show differences in volume and density on fMRI. No clear picture of it
yet.
Functional differences
Don’t know the picture. Some areas have more connectivity (red lines) and some brain areas
have decreased connectivity.
Treatment
Pharmacotherapy
Relieve the symptoms. 2 classes
Stimulants
methylphenidate > inhibitor, largest subscription
dexamphetamine > inhibitor
Often cause decreased appetite, insomnia, tachycardia and nausea
Non-stimulants
atomoxetine > inhibitor
guanfacine (US) > agonist
clonidine (US) > agonist
Often cause nausea and vertigo
re-uptake transporters on the synapse. Methylphenidate blocks the re-uptake of dopamine,
so concentrations are higher in synaptic cleft and less interaction with dopamine receptor.
Atomoxetine targets the noradrenaline receptors in the same way.
Name imaging modalities
Describe the technique behind it
Describe neurological …
Why neuroimaging > clinic (diagnosis/prognosis) and research (improve diagnostics, prediction,
understand biological processes.
How to visualize the brain
1. Structural brain imaging
CT doesn’t give anatomical details of the brain. MRI will allow to see difference between tissues
of the brain.
MRI: Big magnet. Have an antenna (receptor, located above the head of the patient) that
receives signals from the brain, but also sends the signal to the brain. The magnet doesn’t
change. Sometimes difficult to apply due to magnetic force.
- Positives > Non-invasive, non-ionizing radiation, good resolution for different tissue (allows
good discrimination).
- Negatives > Quite time-consuming, contradictions to do with metals in patients (e.g. pace
makers), noise, have to be very specific with what you want to see/how long/etc.
NMR = MRI, less scary name for patients. Antenna sends radiofrequency signals to the brain and
some are released from the brain so you can capture them. Look at the protons in hydrogen
parts (water) of the body. Protons are pointing in random directions normally. When enter MRI,
the magnet will force all the protons to point parallel to the magnet of the machine (no signal
yet). The antenna sends radio pulse towards the brain. This will change the direction of the
protons. When no signal anymore, the proton turns back to original position. That change
releases a signal that is sensed by the antenna. The protons not reacting the same (different
tissues) will not give the same signal (e.g. longer time), which allows to see different parts of the
brain. In research now 0.1 mm resolution.
T1 weighted image gives good contrast between cortex and white matter. Contrast between
fat and water (hyposignal). Good to capture anatomy of the brain. E.g. shows main part of
the tumor (see pic). Can see a bit of edema but cant see the borders very well.
T2 weighted image good at showing us the water. Water now gives hypersignal (very high
signal). Useful to detect pathologies (e.g. tumors because most of them are full of water).
Shows edema very well, but see less brain metastasis (see pic).
Often use combination of sequences to get information on different parts.
FLAIR: fluid-attenuated inversion recovery. Take T2 and reverse the signal coming from the
water. CSF is suppressed. Might be easier to see damaged areas. Want to see damaged areas
where most water is present. Suppresses signal from CSF so you can see the border of the
damage more clearly. Can differ between CSF and lesion. Improvement in ventricle part.
Double inversion recovery: suppress both CSF and white matter signal. To see better contrast
between grey and white matter. Basically get only the grey matter. Lesions will be seen as
hypersignals. Can see what is going on in the cortex.
, DWI (diffusion weigthed imaging): mostly look at white matter (is where lot of diseases have
alterations). Water moves freely in unrestricted fields = isotropic. When water is constrained,
it moves differently = anisotropic. Axons restrain the movement of the water. Detect the way
of the water moving, but indirectly shows the direction of the axons. Can also detect the
amount of movement. If e.g. damaged axon, water moves more freely (more diffusion). Can
tell with the imaging. Can make reconstructions based on mathematical models (because you
don’t directly measure the axons, cant count them with MRI).
Tractography: look at connection and fibers of specific regions.
Ischemic stroke
CT scan often used first. MRI gives bit more information (e.g. where the stroke emerged and
where the edema around it is). MRA (angiography) can detect exactly the position of the
blood cloth (allows e.g. surgeon to intervene).
Imaging in research
Qualitative (pathology)
Quantity (structural connectivity)
2. Functional brain imaging
look at what is going on with metabolism of the brain.
PET: inject radioactive isotope into the body. Need to know exactly what you want to measure.
Different tracers depending on need of clinician. Get gamma signals out of the body that are
detected by a specific camera that is going to reconstruct the brain. Often coupled to CT or MRI
(most often CT) to get the anatomy coupled to the metabolism.
MRS (magnetic resonance spectroscopy): done in MRI scanner. Gives a spectrum of different
metabolites that are detected. No ionizing radiation. Bad for spatial resolution (cant see very
small regions).
fMRI: good at knowing how brain is functioning. Shows functional connectivity. Like DWI, it is an
indirect measurement. Look at blood flow around neurons. Diamagnetic (doesn’t create
magnetic field) when oxygenated and when deoxygenated it is paramagnetic (creates magnetic
field). Gives different signals (called BOLD, slight delay in receiving signal). Look at ratio
oxygenated vs deoxygenated blood. Stimulus is applied > increase neuronal activity > demand of
oxygen > increased blood flow > blood more oxygenated > great imbalance between oxygenated
and deoxygenated > signal is measured. Steps are quite fast, but need to go through them first to
be able to measure something. Signal that is obtained is very low. To have better signal, you need
to do it a lot of times and average it. Therefore, we have block design (tasked-based fMRI). Ask a
patient to do certain tasks and scan what regions are active. Alternate tasks a lot of times.
Negative: weak ability to determine the time course of a response. E.g. patient with MS needs
more signal to retrieve same information as a healthy control, cognitive impaired people cant
reach it. Resting state fMRI looks at activity of brain when you are doing nothing. Can recreate a
lot of networks. Can give idea of how brain functions without needing a specific task. Task based
you are restrained with 1 task. Get an idea of what is going on but only for that task. With resting
state, you capture how the brain functions in general.
MEG (magento…): MEG measures the dendritic activity by measuring magnetic fields. EEG
measures electric fields in axons and dendrites. MEG is ‘better’ because > not influenced by
scalp, takes less time, better signal. D3ivide the signals of raw MEG into different bands with their
own traits. MEG has higher temporal resolution. It is a direct measure of neuronal activity. Poo
spatial resolution, difficult to look at deep brain structures.
,Lecture 2a: Preclinical models of drug addiction
Drugs alter behavior and is used to induce strong emotions. Short circuit into the brains reward
system.
Addiction as psychiatric disorder
Initial use is voluntary. Addiction is a chronic, relapsing brain disease. Changes the brain (PET scan).
Define clinical term is substance used disorder (SUD). Diagnosis has evolved from pharmacological
to psychological related symptoms (change in behavior that are related to taking drugs).
Diagnostic and statistical manual of mental disorders is a ‘bible’ in the US used to diagnose
psychiatric disorders.
Multiple levels of SUD. Changes treatment plan.
Different drugs have different risk levels of addiction. E.g. tobacco (31.9% of people using it will
become addicted) has quite a high risk, whereas cannabis has a lot less of becoming addicted.
Validity criteria for animal models for human disorders (always have some limitations (e.g. ethics))
Construct validity
What changes in human is same as what changes in model. Short exposure to a cue can
activate the brain of someone in abstinence.
PET scan shows higher signal in dopamine receptors when exposed to cocaine environment
in both humans and mice (memory formation is comparable).
Face validity
Model mimics the human disorder. All animals self-administer drug when having the chance
(see chimpanzee example).
Relapse
Long-term relapse rates are high. During abstinence, triggers of relapse are drug (laps
causes relapse), stress (social/physical harm), cues (e.g. advertising). See the same
thing in models (face validity).
Predictive validity
Effect in models should also translate to humans. Most important, but no successful
pharmacotherapies for addiction. Much work to do.
Addiction cycle
Non-problematic/recreational drug use > escalation of drug use (take more than anticipated) >
compulsive/problematic use (keep using it despite the harm it is causing us) > abstinence (stop
because of the harm it is causing) > relapse
Using the mouse model
Group of rats suppresses their alcohol intake after 3 days of punishment (shock). Another groups
doesn’t. different suppression ratio.
Are we actually modeling drug addiction in rodents
Choice procedure > between cocaine and sugar. Animals can only choose 1 lever. Found that the
majority of rats chose sugar over cocaine. Also see the difference in humans (some individuals that
will chose the drug as reward). Question is what defines the difference between the group choosing
drugs and the group choosing the other option.
Drug use often in social context. Social-based voluntary abstinence > instead of giving rat drugs, give
them another rat. Can choose between getting drugs and hanging out with friend. 100% chose the
other rat.
, Lecture 2b: ADHD
Response inhibition is the ability to inhibit your response. People suffering from ADHD perform
worse with this task. Will be more likely to press the red button.
Motivational pathway (reward systems of the brain) also play an important role in the causes of
ADHD. This and the response inhibition theory are thought to be the main causes.
What is ADHD
Persistent, pervasive, extremely hyperactive, impulsive and inattentive.
Validity of diagnosis still under discussion. DSM-V criteria help to diagnose. Important difference
between normal (everyone has the symptoms from time to time) and ADHD is duration and how it
affects your life.
ADHD rarely comes alone. Often accompanied by other diseases (e.g. ODD/CD, depression, anxiety).
Diagnosis
No strict objective criteria. Often by multiple informants (parents, teachers, etc).
ADHD disappearing might have to do with the late maturation of the frontal cortex.
Causes
Genetic risk factors
ADHD clusters within families. 75-80% hereditary. Multiple genes contribute, but no clear
model yet.
Polymorphisms
Dopamine receptors have been linked with ADHD. PET study showed binding affinity for
dopamine transporter is much higher in normal people than ADHD patients because of
functional changes in the activity in the brain of ADHD patients.
Structural differences
ADHD and controls show differences in volume and density on fMRI. No clear picture of it
yet.
Functional differences
Don’t know the picture. Some areas have more connectivity (red lines) and some brain areas
have decreased connectivity.
Treatment
Pharmacotherapy
Relieve the symptoms. 2 classes
Stimulants
methylphenidate > inhibitor, largest subscription
dexamphetamine > inhibitor
Often cause decreased appetite, insomnia, tachycardia and nausea
Non-stimulants
atomoxetine > inhibitor
guanfacine (US) > agonist
clonidine (US) > agonist
Often cause nausea and vertigo
re-uptake transporters on the synapse. Methylphenidate blocks the re-uptake of dopamine,
so concentrations are higher in synaptic cleft and less interaction with dopamine receptor.
Atomoxetine targets the noradrenaline receptors in the same way.
