W7 - Introduction to Clinical Neuroscience

Question 1

How does neuroimaging work?

Answer 1

Brain size is proportional to body size.
Each neuron may be connected to up to 10,000 other neurons.

Question 2

What is the evolution from man to mouse?

Answer 2

The corticle strucure is around 4mm thick and comprised of 6 layers. Convolutions in the brain means layout is bigger.

Question 3

How did the Greek concepts of the brain develop?

Answer 3

The Encephalocentric theory:
- A seat of sensation and understanding
- Interpreter of thing, understanding, emtions, moral and aesthetic activities, souk

The cardiocentric theory:
- Cooling agent of body heat
- Command centre of body
- Heat at centre

“The weight of Greek heritage was enormous. The controversy between encephalocentrists and cardiocentrists continued well into Renaissance and beyond”

Galen used rational investigative methodology and first-rate anatomical skill, Galen reached the conclusion that the nerves and the spinal cord were composed of the same substance of the brain [17] . He also provided a clear demonstration that the spinal cord originated from the brain.

Question 4

What does Clinical neuroscience include?

Answer 4

Neuro:
Brain, spine, peripheral nervous system, gut
stroke, tumours, MS, schizophrenia, depression …………
Input from PNS may alter brain function - chronic pain
Toxins can affect brain function
urea (kidney disease)
ammonia (liver disease)
sugar, alcohol, nicotine ………..
Behavourial / environmental factors can be detrimental
stress, isolation, internet use,
Behavourial factors can boost brain function
exercise, education, enjoyment, engagement …..

Clinical:
Human disease: diagnosis, treatment, mechanisms

Science:
Mechanistic studies, biomarkers, cells to whole-body ……..

Question 5

What are the cellular structures of the brain network?

Answer 5

Skull
dura
SAS space - with arteries supplying blood from CVS. Oxygen supplies penetrate down to the deep grey matter structures.
There is a mix of glial astrocyte cells and neurones in the cortex.
Axons project to white matter and connect to grey matter, cerebral cortex, spine and PNS.

Brain cells:
Cell body -
Dendrites receive signals
Axons transmits the processed signal
Dendrite (grow as you learn) , growth, branching, pruning, plasticity..

Question 6

What are the artificial neural networks for image analysis mimic brain connectivity?

Answer 6

The brain is hardwired too.
Eg, We are proned to seeing two eyes and a mouth.
Pareidolia is the misinterpretation of sensory input.

Computer neural network:
Input image, convolution layer, pooling layer, artificial network corresponds to the excess neuronal presence indicating infarction, haemorrhage, tumour in brain etc as output.

Question 7

What is the STROOP test?

Answer 7

Trying to read colours out loud without reading the word.

Question 8

What are the brain regions of functional localisation?

Answer 8

Map the cortex to:
Sensory homunculus - PNS, sensory info to brain
Motor homunculus - signals to muscles for motor control.
We are verbal and tactile animals - hand controls. We make tools etc.
They did experiments with epileptic patients. Electric shocks to particular parts of the brain that corresponds to control. Eg. they were asked to do finger flections and shocked that part of brain, they found it difficult to do that task after.

Question 9

What is the cases of Phineas Gage?

Answer 9

He was a railway track worker - dynamites into blast rocks to clear way for railway.
Major frontal lobe damage
Personality changes, fitful, irreverent, impatient….

Question 10

What is the Moneiur Leborgne case?

Answer 10

………. nicknamed Tan Tan , for that was the only syllable he could utter (save for a swear word or two), died in the care of the neurologist Paul Broca in Paris on April 17, 1861.
The Broca’s area associated with language was damaged.

Neurological condition - facial ignosia - can’t recognise faces.

Question 11

What did the high resolution 3D MRI of Leborgne’s brain show?

Answer 11

Damage is much deeper than Broca reported from observing the intact
brain, hence why Leborgne’s speech impediments were so severe

Question 12

What is post-mortem pathology?

Answer 12

Glioblastoma – made fr0m glial cells that have become cancerous - highly infiltrative
Hemmorrhagic Stroke –localised damage
Hippocampal sclerosis – structural change.
can cause seizures, found in Alzheimers and other dementias

Question 13

How does medical imaging work?

Answer 13

Firs tmedical X-ray by Wilhelm Röntgenof his wife Anna Bertha Ludwig’s hand in 1895
X-rays are helpful to see bones, but not the soft tissue.

Question 14

What is X-Ray CT?

Answer 14

The X-ray tube rotates around the patient. A beam of X-rays shots gets picked up by detectors on the other side of the body.

This lead to the invention of X-ray CT for the study of the brain. The first CT of a patient was at Atkinson Morley’s Hospital.

Modern day CTs show a lot more detail - able to see skull, blood vessels.
Blood leaking out of the vasculature absorbing x-ray strongly = bright region
Shadow = edematous surrounding region.
This technique just takes up a few mins and gives a contrast agent that absorbs x-rays. Take that intravenously. You don’t get good differentiation between grey and white matters of the brain.

Question 15

What are the magnets within us?

Answer 15

MRI is a soft tissue imaging technique.
We have 75% water in us and water has H2O molecules. The H atoms at their core has a proton, which spins on its own axis letting it have a magnetic moment. The billions of these in the body are what’s used to generate that image.

Question 16

What is NMR to MRI?

Answer 16

These were used before MRI.
A chemical sample was placed between a strong magnetic field, we then have a radio wave input, which interacts with the chemical sample we are interested in. We have a second coil where we pick up the radio frequency output. This is detected and amplified and turned into an NMR spectrum.
The peaks relate to different chemicals and relate to signals coming from sample at different frequencies.

They came up with the idea of picking up signals that relate to the location of the signals. They used a finger.

Question 17

What is the MRI signal source?

Answer 17

A strong magnetic field creates magnetisation in
all the tissue
This magnetisation is from the protons of
hydrogen in water and fat in the tissue
The magnetisation direction can be manipulated
by radiofrequency pulses to produce an MRI signal
to create an image
The intensity in the image depends on water
content, tissue structure, blood flow, perfusion,
diffusion, paramagnetics, T1 and T2 etc

Question 18

What happens along with increased water content?

Answer 18

T2w MRI – signal intensity increases with increased water content.Increased tissue water and loss of cellular structure all lead to increased T2. T2 is a measure of how long the MRI lasts.

Brain tissues shows up darker.

In areas with a brighter signal intensity, in that image the middle cerebral artery shows up bright due to oedema.

High-grade glioma - at the core, there are tumour cells rather than brain tissue. It is a less structured tissue, so it is more fluid and shows up brightly. Surrounding that, there is a region of bright due to the oedema because of more fluid in the tissue. The whole tumour region and the damage to the surrounding tissue shows up bright.

Multiple sclerosis - causes demyelination. You lose the white matter structure and you get inflammation. You get bright spots related to the multiple sclerosis regions.

Question 19

How does an MRI investigate anatomical structure?

Answer 19

These are T1 weighted images.
You put radio frequency signals in that interact with the magnetisation. They are effectively knocking the magnetisation out of alignment and the magnetisation comes back into alignment with the magnetic field.

T1 image is related to the time it takes to realign.
The CFS shows up very dark - takes a long time for magnetisation to align. White matter shows up very bright and grey matter inbetween.

*1mm spatial resolution
*Grey and white matter
*Volumetry
*Degenerative change - like aging and dementia
*Developmental abnormalities - like early development of a child
*Disease specific changes

Question 20

What is Grey and white matter?

Answer 20

Grey:
In grey matter water in both the intra- and
extracellular compartments has relatively
free motion.
- Cell body, dendtrite, H2O intracellular and extracellular

White:
In white matter approximately 50% of the
tissue volume is accounted for by myelin
structures, within which T1 relaxation of 1H
in lipid structures is very short.
Hence the average T1 of WM < GM
- axonal pathways with myelin sheaths which is fatty tissue, CH3 and CH2 in terms of structure.

In a patient with Alzheimer’s dementia, the brain itself has shrunk tremendouslty. CFS spaces in the ventricles get larger and the CFS space between brain and dura also gets larger.

Grey and white matter have very different T1 relaxation times because the water generating the signal are in a different structural environment between the two tissue types. Protons in water moving up and down axonal pathways themselves can exchange with the myelinated protons. This means myelinated protons have a very short T1, reduce the average T1 of the water in white matter.

Question 21

How can you make a surface rendering of the cortex with T1 weighted image data sets?

Answer 21

Aim is to find how the cortex changes with development.

Genes a key early factor in development; environment, education, emotional, nutrition, toxins…all major affectors
Synaptic pruning and myelination changes: sensory & motor systems complete first (pre and early school), higher order functions still developing up to early adulthood.

A baby born at 26 weeks has a much smoother cortex than one born at 34 weeks.

Question 22

How does the brain connectivity work? White matter tracts?

Answer 22

These can be observed via Diffusion MRI.
Looking at the structure of the neurone, there is the cell body and the axon with myelin. Within the axon are neurofibrils with the water that picks up the NMR signal to create the image.

With MRI, you can measure how freely water can diffuse in different directions. Can determine direction of maximum and minimum diffusion. With that info, can work out the orientation of the axon within brain.

These diffusion MRIs show an anisotropy map.
High anisotropy means diffusion is very high in one direction and low in the other.
In grey matter, don’t have myelinated structures = dark
In white matter, very high diffusion orientation and restricted diffusion orientation.

Question 23

What is White Matter Anatomy from diffusion tensor MRI?

Answer 23

Colour coding shows direction of maximum diffusion. Superior to inferior in blue. Anterior to posterior in green and left to right in red.

Question 24

What is a 3D MR angiography of the brain?

Answer 24

Radio frequency passes - Very short TR of about 10ms used - flowing blood provides a high signal against a darker background tissue signal.
Signal in static tissue = very weak
Signal from water in blood flowing through that tissue = high

Important for detecting strokes, in surgical procedures like thrombectomy, it tells whether the surgical intervention has been successful or not.

Question 25

What is Arterial blood and Venous blood?

Answer 25

BOLD fMRI
Increased Glc & O2 extraction
leads to increased blood flow
which leads to reduced Hb
and so an MRI signal increase

Arterial blood = oxygenated
Venous blood = deoxygenated
Deoxyhemoglobin is paramagnetic. Causes variation in the magnetic field decreasing the MRI signal. This means the signal surrounding venous vessels are reduced.
The amount of deoxyhemoglobin related to the amount of extraction of oxygen, which is determined by tissue metablism.

Increased activity in area of brain = more blood flow cuz more glucose & oxygen needs to be delivered. Overall effect = increase in blood flow washes out deoxyhemoglobin. Magnetic field non-uniformity is reduced and MRI signal increases. Active part of brain has increased signal intensity.

Question 26

How does Functional MRI in hand osteoarthritis have features of central pain processing.

Answer 26

Task : rest finger flexion - rest - flexion - rest - flexion

In people without osteoarthritis: this activated somatosensory motor and pre-motor corticles.
In people with osteoarthritis: they experience pain, so activated insula, thalamus, cingulate gyrus (associated with pain perception).

Functional MRI is useful for understanding active brain processes.

Question 27

What is MR spectroscopy?

Answer 27

MR spectroscopy is multiparametric

MR spectroscopy is done with a standard clinical scanner. The patient lies in the core of a strong magnet. Instead of taking an MR image, we can define a small voxel - 1H MRS from a voxel of a 15mm sided cuboid in about 5 minutes we can get a spectrum.

On the graph, the x axis is the frequency measured in parts per million (ppm). y axis is the amount of signal at a particular frequency. Usually the peaks come from different chemicals. Spectroscopy can say a lot about the metabolic processes or changes associated with diseases.

tCho – membrane metabolism,
proliferation
tCr – metabolism, cell density
NAA – neuronal marker - the highest peak
Lipids - necrosis
Glx – neurotransmitters Glu + Gln
mI - glial marker, osmoregulation
Lactate - ischemia

Question 28

Why is Glutamate a major excitatory neurotransmitter?

Answer 28

Glutamate that doesn’t travel across the synaptic cleft of neurones and gets picked up by the receptors gets picked up by astrocytes, which converts to glutamine and is fed back into the presynaptic neuron. Spectroscopy can be used to assess the amount of glutamate and glutamine.

In vivo MRS has demonstrated changes in
Glu and Gln concentrations in:
aging, depression and mood disorders,
epilepsy, genetic disorders, hepatic
encephalopathy, brain tumors, tumefactive
multiple sclerosis lesions, alcohol addiction
and drug abuse, schizophrenia, traumatic
brain injury and neurodegenerative
disorders
Ramadan et al. NMR in biomedicine 2013
Glutamatergic drugs being developed and
assessed in bold above

Question 29

What is the result of MRS of glutamate + glutamine (Glx) in ultra-treatment resistant schizophrenia?

Answer 29

What can we deduce from this data?
* Elevated Glx with worsened disease severity
* Potential biomarker for assessing drug actions/ response
* Less useful as a diagnostic biomarker

Good for understanding metabolic processes that lead to after treatment resistant schizophrenia for example. It would be less useful as a diagnostic biomarker. It would be difficult to differentiate between control groups and patients.

Question 30

What is Molecular imaging with Positron Emission Tomography (PET)?

Answer 30

Radionuclides are incorporated into pharmaceuticals that are specific for metabolic processes or cell receptors. The injected radiopharmaceutical generates a localised gamma ray signal relating to metabolism or cellular function.

We can have radionuclei that emits positively charged electrons (positrons) so it’s radioactive decay. A positron will move through tissue, very small distance before it meets with an electron. A positron will move through tissue, very small distances before it meets with an electron, then there’s annihilation and positive charge to give out two gamma rays in opposite directions.

PET scanners have a ring of gamma ray detectors. The radioactive positrons are injected intravenously, and when the patient lies within the scanner, gamma rays give out in opposite directions. The detectors pick up 2 gamma rays at the same time, we can draw a line through the patient to say the gamma ray was emitted from that point. We can join these lines together to come to a region where we think these annihilations are occurring. It is possible to map out the areas in 2D slices that they are missing radioactive decay, gamma rays.

If you inject a particular pharmaceutical, after a certain amount of time, within the half life, can map out the intensity of the distribution of the particular pharmaceutical you’ve injected.

Question 31

How does Brain perfusion and metabolism
using PET O15 imaging work?

Answer 31

Transaxial parametric images from 4 brain PET scans of a normal subject with 4 different tracers:
O-15 CO –cerebral blood volume (CBV)
O-15 water –cerebral blood flow (CBF)
O-15 oxygen –metabolic rate of oxygen (MRO) and oxygen extraction fraction (OEF)
FDG –metabolic rate of glucose utilization (MRG).

If you are giving these drugs intravenously, there is a rapid increase in signal intensity in the arterial blood. As the radioactive substance is washed into the brain, the blood decreases in secreted via the kidneys.

The brain tissue increases up to a plateau and a slow decrease.
Kinetic model connects arterial to the brain to the venous and out.