WEEK 1 Flashcards
Galen (2nd century)
the brain is the siege of the mind
Da Vinci
studied the brain’s physiology, an early form of structural brain imaging
Lesion studies
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
Angelo Mosso
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.
Wilhelm Rontgen
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.
Walter Dandy
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.
Electroencephalography (EEG)
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
Main uses of EEG in a clinical setting
1) detect and characterise epileptic seizures
2) combined with fMRI, used to identify the whole network of brain regions involved.
Computerised Tomography (CT)
invented by Godfrey Hounsfield
combines X-rays from many directions to reconstruct the volume of interest in slices
Positron Emission Tomography (PET)
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.
Magnetic Resonance Imaging (MRI)
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.
fMRI
“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
Structure vs. Function
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)
Multimodal Imaging
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.
EEG advantages
- cheap and somewhat portable
- measures activity on the millisecond scale
EEG disadvantages
- 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
Magnetoencephalography (MEG)
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
MEG disadvantages
- suffers from low spatial resolution as it measures signals on the surface of the scalp
- medium tolerance level
Functional Near Infrared Spectroscopy (fNIRS)
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
The BOLD effect
Blood
Oxygenation
Level
Dependent
fNIRS disadvantages
- 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
Neuroimaging techniques by price
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)
fMRI: cognitive subtraction
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
fMRI: measuring
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.
fMRI: process
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.
fMRI: processing stream
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.
Darwin’s tree of life
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.
Structural homology
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”
What we can learn from animal models
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
Functional animal studies
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
Baker’s yeast
- 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
Baker’s yeast: functional study
- 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.
The worm (C.elegans)
- 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
John Sulston: C. elegans
- 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.
Kenyon et al. : C. elegans
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.
The fruitfly: drosophilia
- 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.
Forward genetics
we can mutate the genome of drosophilia and look at the phenotype to identify the protein, then finally the gene.
Reverse genetics
find a disease-related gene for example, then identify the protein expressed, and how it relates to the disease.
Mitochondrial dysfunction: drosophilia study
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.
The zebrafish
- 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.
The zebrafish: functional in vivo studies
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
Mutation of CNTNAP2A: A zebrafish study
- 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.
The house mouse
- 90% genes are homologous to human genes - so it is a genetic model organism
Kravitz et al. (2010): Parkinsonian mice study
- 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.
