WEEK 1

Question 1

Galen (2nd century)

Answer 1

the brain is the siege of the mind

Question 2

Da Vinci

Answer 2

studied the brain’s physiology, an early form of structural brain imaging

Question 3

Lesion studies

Answer 3

examine functional deficits after brain damage, generating further understanding of the brain’s physiology.

drawback: info for the precise location of the lesion is only available after the patient’s death

Question 4

Angelo Mosso

Answer 4

pioneer of functional brain imaging. observed and measured brain pulsations in the frontanelles of newborns and in the exposed brains of patients with skull defects.

attempted to measure brain activity by weighing it with a balance: increased bloodflow to the brain, representing cognitive functions, would tilt the scale. this bore resemblance to fMRI.

Question 5

Wilhelm Rontgen

Answer 5

first used X-rays to image the human body.

drawback: imaging the brain this way was far from ideal, as there is a lack of X-ray contrast within the skull.

Question 6

Walter Dandy

Answer 6

invented ventriculography and pneumoencephalography in 1919 to generate contrasts for removing ventricular CSF through a hole in the skull and replacing it with air.

drawback: risky side effects including death lol

in use until the 1970s when CT scans came along.

Question 7

Electroencephalography (EEG)

Answer 7

invented by Hans Berger

milestones:
- first measure of epileptic spikes (1934)
- characterisation of sleep cycles (1953)

characteristics:
- non-invasive (only gel is applied on the skin)
- records brain activity from the surface of the scalp
- signal is picked up by multiple electrodes in different locations

Question 8

Main uses of EEG in a clinical setting

Answer 8

1) detect and characterise epileptic seizures

2) combined with fMRI, used to identify the whole network of brain regions involved.

Question 9

Computerised Tomography (CT)

Answer 9

invented by Godfrey Hounsfield

combines X-rays from many directions to reconstruct the volume of interest in slices

Question 10

Positron Emission Tomography (PET)

Answer 10

most invasive functional technique, needing a very high tolerance, most expensive technique (requires tracers to be produced on site using a cyclotron)

involves tagging an active molecule with a short-lived radioactive tracer that is injected in the body. tracer concentration and location is then computed by detecting the GAMMA rays emitted as a byproduct of the decay of the tracer.

tracers: fluorine 18 (f18) or fluorodeoxyglucose (FDG); required to have a short half-life so they can decay quickly.

Question 11

Magnetic Resonance Imaging (MRI)

Answer 11

used to study brain structure in different ways:

1) higher resolution anatomical scanning

2) looking at microstructural changes with diffusion tension imaging (DTI)

3) mapping white matter tracks in the brain

comes in 2 strengths: 1.5 Tesla (30x stronger than earth’s magnetic field) and 3 Tesla. magnetic field generated is equivalent to the one used in junkyards to lift cars.

field is generated by a superconductive magnet that is always on and requires cooling by liquid helium. patients need to be MRI-compatible (not carrying any metal) before entering the room.

Question 12

fMRI

Answer 12

“modern day phrenology”, the method of choice to study brain function

indirectly measures dynamic changes every couple of seconds in the whole brain during experimental tasks (task-based fMRI) or at rest (resting state fMRI) via regional changes in magnetism

based on the BOLD effect

Question 13

Structure vs. Function

Answer 13

1) structural imaging
- low temporal resolution (minute scale)
- high spatial resolution (high detail)

2) functional imaging
- high temporal resolution (second scale)
- low spatial resolution (low detail)

Question 14

Multimodal Imaging

Answer 14

a typical hour of scanning consists of acquiring several structural scans and a handful of fMRI scans, enabling researchers to look at the problem from different angles.

Question 15

EEG advantages

Answer 15

• cheap and somewhat portable
• measures activity on the millisecond scale

Question 16

EEG disadvantages

Answer 16

• signal is only measured at the surface of the scalp, leading to a lack of localisation of the brain function - especially the deep brain.
• lowest spatial resolution

Question 17

Magnetoencephalography (MEG)

Answer 17

characteristics:

• closely associated to EEG but measures the magnetic fields generated by brain activity on the scalp
• subject has to position head in an MEG helmet
• a vat of liquid helium is used to cool down the sensitive magnetic sensors

Question 18

MEG disadvantages

Answer 18

• suffers from low spatial resolution as it measures signals on the surface of the scalp
• medium tolerance level

Question 19

Functional Near Infrared Spectroscopy (fNIRS)

Answer 19

characteristics:
- non-invasive optical imaging technique
- detects changes in brain activity through neurovascular coupling using near-infrared light
- based on the BOLD effect

• suitable for the infant brain, as it requires very low tolerance and only has a small number of sensors

Question 20

The BOLD effect

Answer 20

Blood

Oxygenation

Level

Dependent

Question 21

fNIRS disadvantages

Answer 21

• near-infrared light does not penetrate deep through the skull of the brain (only about 5 cm)
• limited spatial resolution, also due to the small number of sensors

Question 22

Neuroimaging techniques by price

Answer 22

cheapest to most expensive in terms of equipment cost:
EEG, fNIRS, MEG, fMRI, PET

cheapest to most expensive in terms of running cost:
EEG, fNIRS, MEG (250/hr), fMRI (500/hr), PET (at least 2000/hr)

Question 23

fMRI: cognitive subtraction

Answer 23

principle in which different experimental conditions associated to different cognitive states are statistically contrasted to find out which parts of the brain respond to what is different between the conditions

Question 24

fMRI: measuring

Answer 24

oxyhaemoglobin (O2HB) is diamagnetic (not magnetic) and deoxyhaemoglobin (HHB) is paramagnetic (magnetic). when placed in a magnetic field, oxygenated blood doesn’t impact it, but HHB does.

the brightness in an fMRI image is directly linked to the level of local magnetic perturbation. the more perturbation, the darker the image.

Question 25

fMRI: process

Answer 25

a local increase in brain activity triggers: - initial use of the local pool of oxygen, leading to more HHB than at rest, more magnetic perturbation, and so a darker image. this is the initial dip in the BOLD signal. - this is followed by a larger increase in regional oxygen deliver than what is needed: the local area is flooded by O2HB, so less HHB than at rest, less perturbation than at rest, and the image is brighter.

Question 26

fMRI: processing stream

Answer 26

when we first get the raw data from the scanner we have to preprocess it to remove the effects of head movement, cardiac pulsations, respiration, etc. After this, single-subject level analysis computes where brain activity is in the subject's brain in relation to a given experimental model. Afterwards, we normalize all subjects' brain onto a brain template, enabling us to do group-level analysis.

Question 27

Darwin's tree of life

Answer 27

tree that represents the phylogenetic relationship between species no matter how distantly related we are to an animal/species, a common trace remains - so any new finding can potentially teach us something about ourselves.

Question 28

Structural homology

Answer 28

Darwin: "the relative position or connection in homologous parts; they may differ to almost any extent in form and size, and yet remain connected together in the same invariable order"

Question 29

What we can learn from animal models

Answer 29

we can gain knowledge and understanding about the function of: 1) a gene and its encoded proteins (and different isotopes) 2) how specific genes and proteins interact 3) the signaling pathway and how it works 4) the formation/specification of cell types, tissues, and organs 5) the circuits and networks in the NS and the brain 6) all of the above in relation to disease

Question 30

Functional animal studies

Answer 30

1) mutating, inactivating, or overexpressing a gene/protein 2) finding interacting/binding partners 3) screening for enhancers or suppressors of disease genes or proteins 4) epistasis tests and manipulation of a signaling pathway 5) targeted activation and inactivation of neural circuits 6) regulation and function of behavior + the dysfunction of the above may that may underlie disease

Question 31

Baker's yeast

Answer 31

- a eukaryote - used to conduct very quick experiments - used to discover genes and their function in the regulation of the cell cycle and cell division. this is highly conserved across the animal kingdom

Question 32

Baker's yeast: functional study

Answer 32

- found hat the expression of TAF15 led to aggregate formation and had a cytotoxic effect on yeast. so the accumulation of this protein seems to cause aggregate formation. - this is significant because the human homologue of TAF15 also forms aggregates - leading to the discovery of a novel human disease-related gene.

Question 33

The worm (C.elegans)

Answer 33

- discovery of cell lineages and the clonal origin of cell types and tissues - short generation cycle, creating lots of progeny. - ideal model organism to study to genetic basis of aging

Question 34

John Sulston: C. elegans

Answer 34

- c. elegans is made up of 959 cells. - these invariant lineages, which give rise to the animal, make it possible for us to study cell fate decisions and how they are determined.

Question 35

Kenyon et al. : C. elegans

Answer 35

2 genetic mutations changed the lifespan of c.elegans: daf-2 and daf-16. daf-2 animals live up to 55 days, twice as long as wild-type worms. daf-2 suppresses daf-16, playing a big role in lifespan. during adulthood, high levels of daf-2 cause suppression of daf-16, leading to a normal lifespan. if a mutation causes lower levels of daf-2, leading to the desupression of daf-16, lifespan is extended. daf-2 is an insulin receptor, a universally-conserved receptor involved in nutrition and ageing. daf-2 represses daf-16 which codes for FOXO - both involved in longevity.

Question 36

The fruitfly: drosophilia

Answer 36

- first animal to be fully sequenced: 180 Mb sequenced genome comprising of 4 chromosomes encoding 13,600 genes (humans have 25k). - of those genes, 65% show a structural identity to human genes related to neurological disorders. - short life cycle: 10-12 days at 25 degrees. - like humans, they have upper motor neurons that synapse onto lower motor neurons in the nerve cord, that then innovate the muscles.

Question 37

Forward genetics

Answer 37

we can mutate the genome of drosophilia and look at the phenotype to identify the protein, then finally the gene.

Question 38

Reverse genetics

Answer 38

find a disease-related gene for example, then identify the protein expressed, and how it relates to the disease.

Question 39

Mitochondrial dysfunction: drosophilia study

Answer 39

found that mitochondrial dysfunction has a much more pronounced effect when inactivated in dopamine neurons compared to cholinergic and serotonergic neurons, providing essential clues to the study of Parkinson's.

Question 40

The zebrafish

Answer 40

- vertebrates, closer to us in evolution than insects or worms. - one great advantage is that their embryo is transparent - so you can look at it while it develops. if you use a method to visualise the gene expression or neural circuit, you can see it very quickly: zebrafish hatch in 72 hours and can live up to 3 months.

Question 41

The zebrafish: functional in vivo studies

Answer 41

1) you can look at their naturalistic behavior 2) you can do high-speed behavior tracking 3) you can develop computational models 4) you can do functional imaging of the brain 5) you can manipulate circuits 6) you can do genetics

Question 42

Mutation of CNTNAP2A: A zebrafish study

Answer 42

- mutation of the CNTNAP2A gene has been found to be related to autism and hyperactivity in humans - mutant zebrafish were more active at night, a sign of hyperactivity and ASD. - by applying psychoactive compounds, namely estrogenic phenotype suppressors, they were able to suppress hyperactivity in the mutant zebrafish.

Question 43

The house mouse

Answer 43

- 90% genes are homologous to human genes - so it is a genetic model organism

Question 44

Kravitz et al. (2010): Parkinsonian mice study

Answer 44

- in the parkinsonian mice, if D1 was activated with light, there was movement. if D2 was activated with light, the mouse immediately stopped. This is proof that D1 and D2 neurons are involved in movement regulation. - pre-laser, the mice spent less time ambulating and more time freezing. when the laser was on, the mice spent more time ambulating or conducting fine movement and less time freezing despite their dopamine deficits in the striatum, showing that the loss was overcome by the activation of the CHR2 protein. SO activation of D1 can overcome the Parkinsonian phenotype.