Epilepsy (1)

Question 1

Brain size and neuron count

Answer 1

• Elephant has huge cerebellum- more complicated movements (trunk)
• All speicies show epilepsy
• Head trauma, stoke can increase risk of species

Question 2

What do brain cells do?

Answer 2

• Neurones in the brain are rhythmic- around 300 times per second
• Beta rhythm- rhythm for the posture
• Gamma rhythm- rhythm for movement
• Epilepsy is when the rhythms go wrong

Question 3

What don’t neurons all fire at once

Answer 3

• Excitation v Inhibition
• They are in balance between synaptic excitation and inhibition
  
  • Many synapses on the same neurone- many excitation and inhibition therefore different neurones are kept at different levels from the threshold
  • Anything that changes that balance can cause epilepsy- Strychine; Kainic acid
• There are 30,000 synapses on a typical cell, a mix of Glu and GABA
• No 2 cells will have the same balance of synaptic activity so they are all at a different distance from firing threshold
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Question 4

Spiking activity is STOPPED by GABA inhibition

Answer 4

• When GABA is applied to a neurone, AP firing slows down- the cells then fire at a set rhythm
• GABA not only slows neurones from firing, it also tells neurones when to fire

Question 5

Epilepsy

Answer 5

• 0.5-1% of the population suffers from epilepsy i.e. 450,000 people in the UK
• 2% suffer at least one seizure in their lifetime
• 30,000 new cases each year in the UK
• 30% are refractory to drug treatment
  
  • Lots of them respond at the Beginning and then stop after a while
• 20-30% not improved by surgery
• 1000 epilepsy-related deaths per year
• 50% of deaths are SUDEP
• 60-90% Undiagnosed or untreated in developing countries

Question 6

The basis of the ECG

Answer 6

• If these 6 neurones fire randomly you end up with a relatively flat line
• If they fire at the same time- you see a rhythm as you get additive effect
• When a seizure occurs there is widespread excessive spiking on an EEG- all brain cells are synchronised when they shouldn’t be

Question 7

Pathological synchronization

Answer 7

Question 8

Classification of epilepsies

Answer 8

• Generalised whole cortex bilateral
  
  • Tonic-clonic motor seizures- (grand-mal)
  • Absence few motor signs- (Petit mal)
    
    • If you have either of these types you lose consciousness
• Partial/focal/localised- you do not lose consciousness
  
  • Auras (can be any of these)
  • Visual hallucinations
  • Deja vu
  • Specific motor symptoms (Jacksonian twictch)
    
    • Sometimes partial seizure can spread over a greater area you can lose consciousness

Question 9

Reflex epilepsy

Answer 9

• About 7% of people with epilepsy
• Seizures are triggere: TV; Sunlight through leaves; strobe light; sunlight on water
• 0.001% of suffers have musicogenic seizures
• Other triggers: eating, tooth brushing, smells, chess, reading, sums

Question 10

Why do seizures happen

Neuronal networks

Answer 10

• Brain is a small world network
  
  • Regular you have to pass through every neurone to get across
  • Small world you can skip neurones out
  • Random- No telling how long how many neurones are connected
• Connections all excitatory- Additive effect occurs
• Some inhibitory connections

Question 11

Small world neuronal networks with excitation AND inhibition produce oscillation

Answer 11

• These connected networks with excitatory and inhibitory cells have the elements required to create rhthyms
  
  • GABA cells tell neurones when they can fire

Question 12

Neuronal network oscillations- EEG (electroencephalography)

Answer 12

• Different rhythms have different functions
  *

Question 13

Human EEG in temporal lobe epilepsy

Answer 13

• Tonic phase- everywhere is active- muscle ridge (muscles are stiff)
• Clonic phase- rhythm will slow down
• This lasts around 30s-1 minutes
• Psychogenic seizures- psychological seizure not as many physiological signs- often shown by very long seizures
• Seizures can go straight into another seizure- this is life-threatening and patients need to be comatose

Question 14

Synchronisation of 2 PCs by an interneurons

Answer 14

Question 15

So- why do seizures happen

Answer 15

• Imbalance between excitation and inhibition
• Damage to network and maladaptive response

Question 16

How do we study epilepsy

Answer 16

• Animal model
  
  • Inject a chemoconvulsant
  • Stimulate a brain region repeatedly
  • Use an acute preparation

Question 17

Modeling epilepsy

Answer 17

• Induce seizures in a rat
• Leave them for around 3-4 weeks (latent period- this period they are on there way to becoming epileptic)
• They start having many seizures and are epileptic
  
  • These models are bad because 80% of rats die
  • This often causes the rats to have strokes

Question 18

DRE- my approach

Answer 18

• New, relevant, rodent models (rise, Anti-NMDA, Anti-GABAr, FCD)
• Low intensity models to facilitate study of epileptogenesis in undamaged brain
• Models of drug-refractoriness
• Human tissue studies- the best model for a cat is a cat
• Refine and extend human tissue studies- organotypic human brain culture

Question 19

Reduced intensity status Epilepticus (RISE) induced epileptogenesis

Answer 19

• This takes around 3 months
• Because this is slow we can monitor changes in brain structure
• There is greater variability in rats in terms of number of seizures

Question 20

Epileptogensis

Answer 20

• Brains do not become epileptic overnight
• Sub-clinical changes in patterns of network activity drive maladaptive processes in susceptible networks
• At a critical point, spontaneous recurrent seizures manifest
• Epileptogenesis continues through maladaptation in target networks
• Seizures beget seizures- Gaddum
• AF begets AF- someone who had read Gaddum

Question 21

Epileptogenesis- questions

Question 22

The number of synapses is not changed

Answer 22

• There are no changes in the number of synapses in the brain
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Question 23

The number of AMPA receptors in massively reduced by seizures

Answer 23

• The results show that it is the number of excitatory receptors in the brain decrease
• In the 3 months, it takes to become epileptic the hippocampus will not be able to stimulate- No seizures= no excitation

Question 24

Latent period CA3 is hypoexcitable when challenged with 100 nM KA

Answer 24

Question 25

Epileptogenic involved homeostatic synaptic scaling

Answer 25

• When a memory is made new receptors are inserted into the synapses- therefore strengthening the synapse
• Alcoholics- lots of GABA meaning the brain puts lots of excitation within the synapses
  
  • On acute cessation of alcohol, we lose GABA potentiation leaving lots of excitation= seizure
• In the rat model, the excessive excitation- lots of inhibitory receptors- as they normalise epilepsy then sets in

Question 26

Epileptogenesis involves homeostatic synaptic scaling

Question 27

Synaptic scaling is linked to intrinsic excitability

Answer 27

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