Neurological & Psychiatric Disorders
Lecture 1: Brain Imaging
Structural brain imaging
- Structural imaging is used to quantify brain
structure using e.g. voxel-based morphometry. It
can identify the effects of a stroke, locate cysts
and tumors, and find swelling and bleeding or
disease-related lesions.
- A CT scan doesn’t show anatomical details
between different parts of the brain, while an MRI
will allow you to capture different tissues in the
brain.
- Magnetic Resonance Imaging (MRI):
o It’s a non-invasive medical imaging test that produces detailed images of the brain using a
large magnet and radio waves. Radio waves are sent to and released from the brain.
o First, all protons are randomly positioned. Every proton has its own spin (vector); the direction
and strength of a proton’s spin determines its magnetic and electrical properties.
▪ When entering the machine, protons are forced to redirect themselves parallel to the
machine’s magnet. Then, the antenna sends a radio pulse towards the brain. Once the
radio pulse achieves the protons, it will move them almost orthogonally.
▪ As the radio waves are turned off, the protons return to their original position and send
back radio signals via an antenna (receptor), which then are converted into an image.
o Advantages of MRI: (1) non-invasive, (2) non-ionizing radiation, (3) high soft-tissue resolution
and discrimination between tissue types, and (4) morphological information as well as function
information.
o Disadvantages of MRI: (1) time-consuming, (2) contraindications for MRI, (3) noise, and (4)
sequence needs to be adapted to question.
▪ Contraindications: pacemaker, pregnancy, bullet wound, and/or metallic fragments.
- Main ‘techniques’ in MRI:
o T1-weighted MRI (A) shows neuroanatomical changes and
enhances the signal of fatty tissue (white) and suppresses
the signal of water/CSF (hypo signal: black) (good
contrast).
o T2-weighted MRI (B) enhances the signal of water (hyper
signal: white) and is useful for detecting pathologies
because most of them are full of water.
o Fluid-Attenuated Inversion Recovery (FLAIR) (C) is a
T2-weighted MRI technique that shows changes related to
water. It’s trying to suppress the signal coming from
cerebrospinal fluid (CSF) to see damaged areas.
▪ With only T1-weighted MRI you can’t see borders.
With FLAIR, it’s obvious because of more contrast.
o Double Inversion Recovery (DIR) (D) is an MRI technique
used to suppress signals from two different tissues (CSF/white matter) or to suppress a signal
that moves between two pulses.
, ▪ Useful for looking at the cortex, e.g. for pathologies like MS, to see lesions/plaques in
white matter or between grey/white matter. If there are any lesions there, you’ll see
them as hypersignal.
- MRI: Diffusion Weighted Imaging (DWI):
o Diffusion-weighted MRI is based on measuring the random Brownian motion of water
molecules within a voxel of tissue. It will mostly capture what’s going on in the white matter of
the brain, because lots of diseases have alterations there, such as Alzheimer’s and
Parkinson’s.
o Water is either moving freely in unrestricted fields (isotropic) or is restrained from moving in a
certain direction because of obstruction (anisotropic).
o White matter consists of a lot of axons that are going in a certain direction. This technique
captures the water molecules but indirectly also captures the direction of the axons.
▪ Comparing a person with and a person without Alzheimer’s to look at the integrity of
the white matter between the two.
o The amount of movement can also be captioned. If the water is moving more freely, there is
more diffusion, which is a predictor of damaged axons.
- Structural networks:
o Structural connectivity describes anatomical connections linking a set of neural elements,
mostly referring to white matter projections linking cortical and subcortical regions.
▪ It quantifies the number of axons between two brain regions.
o Tractography is a brain imaging technique that describes the mapping of the location and
direction of white matter bundles and their fibres that connect different parts of the brain.
- Comparing modalities (ischemic stroke):
o CT-scan will allow you to have a good look at
the stroke and degree of damage.
o With an MRI, you’ll see where the stroke
emerged and oedema around it.
o With MRA, you can detect the exact position of
the blood clot, allowing for intervention.
- Brain imaging in research:
o Qualitative research is standard in clinical practice and is used to look for pathology.
o Quantitative research uses numbers as output, tries to understand biological mechanisms, and
compare patient groups to healthy controls.
Functional brain imaging
- Functional imaging is used to study brain function and metabolism, often using fMRI and other
techniques such as PET and MEG.
- Positron Emission Tomography (PET):
o A positron emission tomography scan is an imaging test that can help reveal the metabolic
or biochemical function of tissues and organs, by looking at blood flow, neurotransmitters, and
radiolabelled drugs.
o It uses a radioactive drug (tracer) attached to a radioisotope, injected into a vein, to show both
typical and atypical metabolic activity. There are different tracers for different purposes: 18F
(fluoride) to detect cancer, 11C (carbon), and 15O (oxygen) to measure blood flow.
o There are gamma rays emitted from the brain, which are detected by specific gamma cameras
to form a 3D image.
o The result is usually combined with a CT (PET-CT) or MRI (PET-MRI); a PET-MRI can give a
very good location of the metabolic processes in the brain.
- Magnetic Resonance Spectroscopy (MRS):
o Magnetic resonance spectroscopy compares the chemical composition of normal brain
tissue with abnormal tumor tissue. The scan is done in the MRI scanner, but instead of giving
an image of the brain, it gives a spectrum of different metabolites (choline, creatine, GABA,
glutamate, and glutathione).
, o Distribution of electrons within an atom causes nuclei in different molecules to experience a
slightly different magnetic field. This results in different resonant frequencies, which in turn
return a slightly different signal.
o It’s quite specific in soft-tissue contrast but bad for special resolution; it’s not possible to see
within a small region. There is no ionizing radiation used.
- Function MRI (fMRI):
o With a function MRI, small changes in blood flow that occur with brain activity are measured
(indirectly) and it is good for knowing how different brain regions are functioning. It is not
looking at neuron activity directly, it’s looking at the blood flow around different neurons.
o It evaluates blood flow in the brain called the blood
oxygenation level-dependent (BOLD) contrast
technique. It measures the hemodynamic response
of neuronal activity. When there’s a decrease in
neural activity, there is a need for more oxygen in the
brain. This results in an increase in blood flow and
blood oxygen in the surrounding area.
▪ There is a great imbalance between
oxygenated-deoxygenated haemoglobin.
o This technique is indirect and slow.
- Task-based fMRI (block design):
o Measuring BOLD signal changes between task-stimulated states and control states in task-
based fMRI. During the process, one or more tasks are performed to make a signal.
▪ Lots of signals are needed from the fMRI to combine them and make the final signal.
o Block design is powerful in detecting activated
voxels in the brain. In the process, it’s either
alternating two tasks (alternating block design) or
alternating two tasks with another task (controlled
block design). This technique has a weak ability to
determine the time course of the response, which is
the summation of haemodynamic responses in time.
- Resting-state fMRI:
o A resting-state MRI is acquired in the absence of a task. It measures spontaneous low-
frequency fluctuation in the BOLD signal to investigate the functional architecture of the brain.
o It’s possible to recreate a lot of networks that are already known, because of task-based fMRI.
o It gives an idea of how the brain is functioning without having to use a specific task.
- Magnetoencephalography (MEG):
o Magnetoencephalography is a non-invasive test that measures the magnetic fields produced
by dendritic activity in the brain. It’s performed to map brain function and to identify the exact
location of the source of epileptic seizures.
▪ The MEG also measures pyramidal cells that are in groups in the same orientation in
the cortex.
▪ The electroencephalogram (EEG) measures electric fields in axons and dendrites.
o Magnetic fields of the MEG are not influenced by the scalp of skull (hair gel, sweating) but are
still influenced by metal. It takes a lot less time and needs no ‘reference channel’ (better signal)
in comparison to the EEG.
o Right-hand rule: signal is measurable from ~50.000-100.000 neurons firing together.
▪ Axons poor signal: opposing magnetic fields from neighbouring ascending and
descending axons.
o The bands:
, o Why not just use fMRI? MEG has a higher temporal resolution than fMRI, meaning that some
fast functional changes in the cortex are only seen with MEG. On the other hand, MEG is a
direct measure of neuronal activity but has poorer spatial resolution than fMRI.
Lecture 2A: Preclinical Models of Drug Addiction
- Introduction:
o Basic concept: 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.
o Problem: however, in complex human disorders such as addiction, success has been limited
for various reasons indicated in this lecture.
- What is a drug and why do we take them?:
o A drug is any chemical substance that causes a change in an organism's physiology or
psychology when consumed.
o There are legal (caffeine, nicotine, and alcohol) and illegal drugs, such as methamphetamine,
cocaine, and heroin; illegal ones cause a lot of harm, both societal and physical.
o Recreational non-pathological drug use is the intake of natural or synthetic substances for
their psychoactive properties; this is a behaviour widely represented in humans.
o Taking drugs is a form of recreational activity in which brain activity is modified through specific
pharmacological compounds. People take drugs as a behaviour that induces strong emotions.
▪ A large number of recreational activities (non-drug) also induce strong emotions and
strongly alter brain activity without any drugs being involved.
- What is addiction?:
o The clinical term now used for addiction is substance use disorder (SUD). Approximately
5.9% of deaths worldwide are caused by addiction (0.5 million in The Netherlands) and direct
health costs are up to €7.8 billion/year.
o The diagnosis of drug addiction has progressively evolved from pharmacology-related
symptoms to psychology-related symptoms.
▪ Pharmacology-related symptoms are those directly related to effects of drugs on body.
▪ Psychology-related symptoms cause a change in the individual’s psychology or
behaviour because of drugs.
o The initial decision to use drugs is voluntary, but addiction is a chronic, relapsing brain disease.
▪ This is because of a change in the brain associated with a history of drugs.
o Criterion for substance use disorder diagnosis (DSM-5):
▪ Using for longer periods, or larger amounts, than intended.
▪ Wanting to reduce use, yet being unsuccessful in doing so.
▪ Spending excessive time getting/using/recovering from the drug use.
▪ Cravings so intense it is difficult to think about anything else.
▪ Continued use despite problems with work, school, or family/social obligations.
▪ Continued use despite interpersonal problems.
▪ Important and meaningful social and recreational activities given up or reduced.
▪ Repeatedly used in physically dangerous situations.
▪ Continued use despite awareness of worsening physical and psychological problems.
▪ Tolerance.
▪ Withdrawal.
o The severity of SUD is defined as mild (2-3
symptoms), moderate (4-5 symptoms) or severe (6
or more symptoms).
o Different drugs have a different ‘risk’ of addiction.
This picture shows the transition from the total
population that has ever used a substance to the
population that is dependent on them.
- Validity criteria for animal models for human disorders:
o Construct validity: the model should be based on the same physiological and neurobiological
mechanisms as the human disorder.
▪ What’s changing in the human is the same as what changes in the model.
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