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Samenvatting Neurological and Psychiatric Disorders
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BRAIN IMAGINGNeuroimaging is used in the clinic and for research. In the clinic, it is used for
diagnosis and prognosis, which are CT, MRI, MRA, MRS, PET, X-ray, etc. In
research, neuroimaging is used to improve diagnostics, predictions and
understand biological processes (using advanced imaging techniques).
Structural brain imaging: MRI
Structural brain imaging is a type of brain imaging that visualizes the various
structures of the brain and any physical abnormalities that may affect them. It can for example be used to
identify the effect of a stroke, locate cysts and tumors, find swellings and bleedings or other disease-
related lesions.
Different types of structural brain imaging are often combined together. The CT of a hemorrhage shows
the bleeding, but not the precise location. The MRI shows different anatomical aspects of the brain and
the precise location can be defined. The MRI also allows to capture different types of tissues (such as
necrotic tissue).
An MRI machine is a big, strong magnet. An antenna captures the signal (radiofrequency signals) that is
coming out of the brain. The antenna also sends a signal itself. It is a magnet that doesn’t change. There
are special antennas for different body parts. Inside the MRI room, nothing is allowed that can be
attracted to the magnet. MRI images are based on the density of protons from hydrogen particles (H+).
The advantages of MRI are that it is non-invasive (not cutting), uses non-ionizing radiation, has high soft-
tissue resolution, can discriminate between tissue types and gives morphological information as well as
functional information. The disadvantages of MRI are that it is time-consuming, there are multiple
contraindications for MRI (types of metal/pacemakers inside patients, so no MRI possible), makes a loud
noise and it needs to be specific for what needs to be imaged, why and how long.
Every proton has a physical particularity called spin. It spins around a main vector, which is the small
electric field of the proton. At rest, all protons are randomly positioned (total is always 0). When the
magnet turns on, all spins are forced to be redirected parallel to the direction of MRI magnet. Until now,
there is no signal. The antenna sends a radio pulse towards the protons. This changes directions of spins
and makes them almost orthogonal. When the signal stops, protons go back to their parallel position
(under influence of magnet) and during this, a radio pulse is released that is captured by the MRI. Each
type of tissue has a different duration of going back to parallel position and sends out different signals.
T1-weighted image T2-weighted image FLAIR DIR
,T1-weighted images show contrast between grey (cortex) and white matter, due to difference between
fat and water. The black in the MRI is the hypo signal, which is the CSF (water). T1-weighted images
provide anatomic detail. T2-weighted images show hypersignal (white), which shows the water (CSF).
This can be used to detect water in ventricles, which happens a lot in pathology. So, T2-weighted images
are sensitive for detecting fluid and edema. What one wants to see determines what sequence will be
used. Often, a combination is used to get the whole picture (e.g., brain metastasis with edema).
For fluid-attenuated inversion recovery (FLAIR), T2 weighted images are used and the signal coming from
the water (CSF) is suppressed (will turn black). This makes it easier to see damaged areas near regions
where lots of water is present. It enhances the sight on the ventricles. FLAIR shows clear borders
between the edema and the ventricles.
Double inversion recovery (DIR) suppresses both the CSF and the white matter signal. This is used to look
at the cortex (grey matter). It shows lesions in the white matter or between white and grey matter.
All MRI’s are 1 mm resolution. 0,1 mm resolution MRI has only be achieved in research.
Structural brain imaging: CT, DWI, etc.
A CT is mostly used as first modality. However, the MRI shows more information. In the case of a stroke,
the MRI shows where it emerged (which is death tissue with edema around). A MRA shows the exact
position of the blood cloth. Qualitative imaging is standard clinical practice and used to look for
pathology. Quantitative imaging is used in research to understand biological mechanisms and compare
patient groups to healthy controls.
Diffusion weighted imaging (DWI) mostly captures what is
going on in the white matter of brain. It is altered in many
different diseases. Water moves freely (Brownian motion) in open space. This is
called isotropic. In anisotropy, the water is constrained by something and not able
to perform Brownian motion. The white matter is consists of a lot of axons from
neurons, which have a certain direction. By imaging the water, indirectly, the
direction of the axons are imaged. This is because the water is forced to move in the
same direction. There is an amount of diffusion possible, which is a certain amount
of movement in other directions than the direction of the axon. In diseases with damaged or
disappearing axons, this is shown on the DWI. There is more free motion in certain directions in these
cases. Each point in the brain has a main direction. Looking at integrity of white matter in healthy people
and Alzheimer’s patients shows damage in white matter. This is used to pinpoint white matter areas that
are damaged during course of disease. DWI doesn’t directly measure axons, but the water around it.
Structural networks are based on mathematical models. With MRI, the amount of axons can’t be actually
counted.
Tractography looks at fibers that connect regions of brain, which can be reconstructed with DWI.
Functional brain imaging
Instead of looking at the anatomy of the brain, functional imaging looks at how the brain functions (e.g.,
metabolism). Positron Emission Tomography (PET) is used a lot. A radioactive isotype (radiotracer) is
inserted in the body (mostly in artery) and measures metabolic processes. Not every radiotracer
measures the same thing. Gamma signals are coming out of the body, which are detected with specific
cameras. Usually, PET is coupled to CT or MRI. This is because PET is bad at anatomical locations, for
which structural imaging is needed.
,Magnetic Resonance Spectroscopy (MRS) is a special type of MRI. It generates a spectrum instead of an
image of the brain. It gives the metabolite concentrations in the brain. This type of imaging uses no
ionizing radiation. Such as PET, it is bad at anatomical positions.
Functional MRI (fMRI) is good at knowing how the brain is functioning. At the end, it shows functional
connectivity. It is an indirect measure, because it doesn’t look at neuron
activity directly, but at the blood flow
around different neurons. Hemoglobin
is diamagnetic (doesn’t create magnetic
field) when oxygenated. When it is
deoxygenated, the hemoglobin is
paramagnetic, which means that it will
create a magnetic field under the influence of a magnet and form a signal.
fMRI shows the change in the ratio between oxygenated and deoxygenated hemoglobin. This is the
BOLD-signal, which follows when a stimulus is applied. This stimulus creates a demand for oxygen, due to
the increase in neuronal activity. There is an increase in blood flow, which disturbs the ratio between
oxygenated and deoxygenated hemoglobin. fMRI captures the consequence of neuronal activity. The MR
signal obtained is very low. A lot of signals combined are needed. To achieve this, there is alternated
between a lot of tasks, a lot of times. This is done with a block design, which is powerful in detecting
activated voxels, but it is weak in determining the time course of the response and it is quite slow.
Magnetoencephalography (MEG) measures the dendritic activity by measuring the magnetic fields that
are created around them. An EEG measures the electric fields in axons and dendrites. In contrast to EEG,
MEG is not influenced by the scalp or skull, but still influenced by metal from fillings, braces or hair dye. It
takes a lot less time than EEG and needs no reference signal. It gives a better signal than EEG. However, it
is quite bad for spatial resolution.
An MEG measures pyramidal cells, of which there are many in the same orientation in the cortex. It
measures dendrites, which fire longer and this gives more time to measure. The magnetic field in the
brain is the current flowing through the axons. Every current creates a magnetic field. The signal is
measurable from 50.000-100.000 neurons firing together. Axons give a poor signal, because magnetic
fields from neighboring ascending and descending axons cancel each other out. MEG is used instead of
fMRI, because MEG has higher temporal resolution and some fast functional changes in the cortex can
only be seen with MEG. MEG is a direct measure of neuronal activity, but it has poorer spatial resolution
than fMRI.
fMRI is mostly task-based, in order to know which regions are activated by the task. There is also resting
state fMRI. It looks at the brain in rest and measures activity. It shows how the brain is functioning in rest,
with or without pathology. With task-based, there is restriction to one specific task. In order to apply
task-based, the patient should be able to follow instructions.
DRUG ADDICTION
Animal models are essential to improve our understanding of mechanisms underlying human disorders
and diseases. They are necessary to identify drug targets for optimal treatments of the disorder rather
than associated symptoms. However, in complex human disorders such as addiction, the success has
been limited for various reasons.
Addiction as psychiatric disorder
The intake of natural or synthetic substances for their psychoactive properties is a behavior widely
represented in humans. It is known as recreational nonpathological drug use. A large number of
recreational activities (non-drug) strongly alter brain activity. Taking drugs are another form of
recreational activity in which brain activity is modified through specific pharmacological compounds. It is
well known that the initial decision to use drugs is voluntary. Because drugs act directly in the brain, they
, can cause much damage. It causes changes in the brain, which makes it a brain disease. About 6% of
deaths worldwide can be attributed to drugs.
The clinical term for drug addiction is substance use disorder (SUB). The diagnosis of drug addiction has
progressively evolved from pharmacology-related to psychology-related symptoms. Pharmacology
related symptoms are the direct effects of the drug (tolerance and withdrawal). Psychology related
symptoms are changes in people’s behavior due to changing mind (criterion 1-9 of symptoms). The
criteria for a substance use disorder diagnosis are:
1. Using for longer periods, or larger amounts, than intended.
2. Wanting to reduce use, yet being unsuccessful doing so.
3. Spending excessive time getting/using/recovering from the drug use.
4. Cravings so intense it is difficult to think about anything else.
5. Continued use despite problems with work, school or family/social obligations.
6. Continued use despite interpersonal problems.
7. Important and meaningful social and recreational activities given up or reduced.
8. Repeatedly use in physically dangerous situations.
9. Continued use despite awareness of worsening physical and psychological problems.
10. Tolerance.
11. Withdrawal
The severity of the SUD is defined as the number of symptoms. A mild case has the presence of 2 to 3
symptoms. When having 4 to 5 symptoms, it is a moderate case and a severe case has 6 or more
symptoms.
Different drugs have a different risk of addiction. From all the people that ever used tobacco, 31.9%
became addicted (highest of all drugs). For cannabis, this risk is only 9.1%.
Validity criteria for animal models
Animal models should have validity criteria for human disorders. An animal model is never going to be
perfect. All mammals are built on same plan. Also, humans and rodents have homologous brain regions.
Human brain Rat brain
Often, connectivity between the regions is also the same. A study in an animal model can be tightly
regulated, in contrast to humans (also question about ethicality). The validity criteria are:
Construct validity: The model should be based on the same physio-logical and neurobiological
mechanisms as the human disorder.
o Same brain regions and neurobiological systems are activated in laboratory animals and
humans
o Compulsive behaviors, and individual differences
o Compulsive drug seeking is defined as seeking and taking drugs despite the obviously
deleterious effects of doing so
Face validity: The model should sufficiently mimic both the origins and the symptomatology of
the human disorder.
o All animals self-administer drugs
o The triggers of relapse are the same in animal models
Predictive validity: Treatments that are effective in humans should also be effective in the animal
model, without false positive and false negative drug effects.
o To date, there are no successful pharmacotherapies for addiction
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