Final Flashcards
Epilepsy
Epilepsy is characterised by recurrent (2 seizures within a 48 hour period) unprovoked seizures - due to atypical, excessive or synchronous neuronal activity in the brain
Seizure
a change in brain activity; very strong spontaneous activity across the whole brain
Strong activity that causes more strong activity over and over
Due to strong activity, activity becomes in sync with one another
Diagnosis heavily relies on EEG
Very poor and course recording of brain activity with lots of noise
Preictal
prior activity seen before a seizure; may give some sort of cues that the seizure is coming
Ictal
seizure itself
Interictal
time between seizures
Interictal pattern often has distinct patterns that emerge in EEG
Any seizure over 5 minutes -> need intervention
Despite “unprovoked” in the definition,evidence suggests it might be otherwise
Somewhere around 50% of patients will report that seizures are not truly unprovoked
There are some things that are much more likely to provoke a seizure than other things - different phenomena among some people
E.g. factors that may predict a seizure: stress, sleep deprivation, fever, fatigue, heat/humidity, flashing lights, caffeine, fasting, alcohol
Epilepsy is common
(~1%)
People often have it in childhood and spontaneously resolve or comes back
We do not have drugs to target the epilepsy - but we can target the likelihood of seizures (anticonvulsant drugs)
anticonvulsant (anti-seizure) drugs
but not anti-epileptic drugs
Anticonvulsant drugs are often ineffective
ineffective in 30% of people with epilepsy - cannot be treated in pharmacological way
50% of people respond to the first drug they are given for epilepsy and fewer % of people respond to 2nd anti-seizure drug and even fewer % of people respond to the 3rd drug
If you do not respond to the 3rd drug, you will likely not respond at anticonvulsant drugs
Seizure vs. convulsion
an important distinction
Seizure is not a convulsion
Seizures sometimes misdiagnosed as having daydreams as children when in actuality they are having seizures
Convulsion (rigidity and tremors) is only in tonic-clonic
Stigma is extremely common with epilepsy
People think maybe demons
Suicide rate is 2-5 times higher in people with epilepsy, especially from individuals who do not get any benefit from anti-convulsant drugs
Epileptic aura
psychological phenomena that precedes a seizures
Can take variety of forms: bad smell, feeling (pressure/emotion), change in vision, changes in heart rate and palpitations
Epileptic aura
2 important reasons
- can learn to recognize the seizure and get out of harm’s way
- The type of aura you have is probably related to the brain area of where the epileptic focus is (where the seizure begins) - can identify where the epileptic focus is
Focal seizure
does not involve the entire brain. Usually localized to a single brain area - focal single brain area
- Simple partial seizure
- Complex partial seizure
Complex partial seizure
Patients engage in compulsive, repetitive, simple behaviours (automatisms) and more complex behaviours that can appear perfectly normal
Disruption and/or alteration of consciousness is common
Major disruptions of consciousness, Picking
Lost or not entirely there
More complications behaviours
Simple partial seizure
symptoms are primarily sensory or motor or both
Typically no loss of consciousness
Not as disruptive as any of the other types of seizures
Feel a change in consciousness and awareness
colours in vision, and heartbeating
Changes in numbness in sensation
Loss of motor control for a short amount of time
Diagnosis is a challenging
Generalized seizure
involves the entire brain of synchronised brain activity
- Absence seizure
- Tonic-clonic seizure
Tonic-clonic seizure
loss of consciousness, loss of equilibrium, violent tonic-clonic convulsion.
Tongue-biting, urination, and cyanosis (going bluish from lack of oxygen) are also common
Extreme rigidity and rapid tremors
Things that keep you safe are at risk -> not breathing properly: hypoxic -> can lead to stroke or further damage to brain tissue
Absence seizure
no significant convulsion
The primary symptoms are: loss of consciousness, cessation of ongoing behaviour, vacant look, fluttering eyelid
Often No sensation of having lost consciousness
Brief interruption in their conscious experience
Characteristic shape of the EEG wave: Bilaterally symmetrical 3-per-second spike-and-wave discharge
Commonly misdiagnosed (“daydreamer”)
Common in children - and often spontaneously goes away
Can range from seconds to minutes
Secondary generalization
when a focal seizure evolves into a generalized seizure
Most seizures start at a focus but strong intense activity will spread out
What to do if someone is having a seizure?
Do not walk away
Comfort calmly
What to do if someone is having a seizure with convulsions?
Never touch them Ease person to the floor Clear area around them - soft around head Start timer - under 5 mins okay loosen anything tight
General risk factors Epilepsy
Epilepsy is best understood as a collection of individual disorders that share an abnormal tendency to cause epileptic seizures, consisting of dozens of epilepsy syndromes
People who had epilepsy as adults often had it as kids
People who have had blows to head (head trauma) - epilepsy may develop after latency period (often 10 years)
Tumours or strokes may have a higher likelihood of developing epilepsy
65% epilepsy of unknown origin - epilepsy is the end result of a variety different processes
There are a bunch of individual disorders that all end up leading to seizures
Seizures and head injury
(~10-12%)
Immediate seizures = occurring within 24 h after injury to head
Early seizures = occur less than 1 week after injury
Late seizures = occur more than 1 week after injury
Latent period = time between injury and onset of late seizures even years
E.g. Phineas gage died of epilepsy so strong 12 years after head injury
Comorbidities
People with epilepsy are more likely to experience the following co-existing medical conditions:
Diabetes Major depressive disorder - perhaps due to different outcomes from having epilepsy Anxiety disorders Migraine headaches Stroke Heart disease Asthma Arthritis Higher rates of Suicide - especially if treatement in ineffective
Common treatments for epilepsy
- Anticonvulsants
- Vagus nerve stimulation
- Ketogenic diet
- Cannabidiol (CBD)
Anticonvulsants
Overall lowering the baseline activity
Some target and diminish the activity of voltage-gated sodium channels -> channels involved in creating APs
Some target and diminish the activity of voltage-gated calcium channels -> involved in NT release
Some target and block activity on NMDAR, and glutamate receptors -> block excitation
Some target and facilitate activity of GABA -> either cause more GABA to be released or activate the GABA receptors -> more inhibition
Successful in many individuals but not a guarantee
Often side effects, unfortunately - must maintain as low of dose as possible
Anticonvulsants
Four categories of side effects
- Problems with motor speed, cognitive speed - physically and mentally slower
- Impairments to memory
- Problems with mood
- In some cases the development of psychosis- emergence of positive symptoms: delusions, hallucination, disorganised thought, speech and behaviour
- For severe intractable epilepsy, surgical procedures are sometimes required
No brain is better than bad brain
Vagus nerve stimulation
both sensory and motor
Statistically minor benefits but no idea why they are beneficial
Ketogenic diet
High fat, low carb -> producing ketone body
Common in individuals with epilepsy and recommended to switch diets
More effective than vagus nerve stimulation
Cannabidiol (CBD)
Extremely mild in subjective experience - does not make you feel high
Few side effects
Decreased severity and frequency of seizures
More effective than ketogenic diet
epilepsy surgery procedure
Prior to surgery, electrodes are sometimes inserted into/onto the cortex to find the epileptic focus.
Science (and society) have benefited greatly from research with these patients
The halle berry neuron
The epileptic focus is much more likely to be found in the
frontal or temporal lobes than other parts of the cortex.
Why?
L&M
L&M
Brain dysfunction affecting memory
Types of amnesia
Retrograde amnesia is more common but typically for more recent memories than for older memories
Early childhood memories are not lost most of the time -> consolidated many times
Damage to hippocampus or medial temporal lobe -> can lose the ability to form new memories (anterograde amnesia)
Injury is preventing you from laying information down your long term memory
L&M
Brain dysfunction affecting memory
Patient HM
Bilateral medial temporal lobectomy to treat very severe epilepsy (seizures stopped)
Causes anterograde amnesia - eliminated his ability to form new memories
Symptoms seem especially (but not solely) related to hippocampus loss
Some of his hippocampus was in tact -> when they sliced his brain post mortem
HM’s symptoms
Profound anterograde amnesia ->
Some retrograde amnesia - recent memories prior to injury
BUT not all memory affected
Childhood early memories and most past memories were intact
He was holding onto memory in the short term -> working memory which allowed for conversation
Memory duration
Working (aka short-term) memory
E.g. HM could perform digit task (7 +/- 2 digits - normal working memory)
Working memory is the holding space -> space where you hold memory for a bit
Have ability to manipulate and work with the information in working memory
Memory duration
Long-term memory
HM could not consolidate
He had long term memory but lost the ability to transfer memory to long term
Information processing model
Sensory information from stimuli -> stored briefly in sensory memory -> sensory memory is encoded into working/short-term memory -> short term memory is laid down in our long term memory by consolidation
We can rehearse information in our working memory to actively try to keep it in memory longer
Once the information is in long term memory - we can retrieve memory from long term into working memory and remember and work with the memory again
By reworking the long term memory in working memory -> we can reconsolidate it
Hippocampus must be important in mediating consolidation into long term memory
Consciousness & memory
HM
HM’s memory was not impaired for: -> these memories are outside of hippocampal processes
Mirror drawing test
using a mirror image as a stimulus is difficult but error rate goes down over time
E.g. must draw star and you must draw the lines of the star within in some sort of border
Over progressive days, HM’s error rate for the drawing went down
Skill learning is separated out from even learning
Pavlovian conditioning
classical conditioning - eye puff test: play a tone right before puff goes in eye, reflex to make our eye squint
Over time the tone will elicit the blinking
HM had conscious awareness of doing this task multiple times
Pavlovian conditioning is happening out of his conscious awareness
Priming
we are able to generate and retrieve information based on very few cues
You could patient HM a list of words and ask them what words were on the list -> he would not remember
But if you asked him to fill out a word that starts with S and ends with P, he would use the word he was primed with
Explicit memory
memory in our conscious awareness that can be recalled
E.g. remembering what you ate or wore
Implicit memory
influences us but we do not have direct automatic conscious access to it
E.g. muscle memory (riding a bike), skills, habits, classical learning
Muscle memory: skills, habits - important player is the motor system (Cerebellum and the basal ganglia)
Another case with anterograde amnesia and some retrograde amnesia -> motorcycle veered off and crash
motorcycle veered off and crash with TMI and hematoma leading to substantial damage to his medial temporal lobe
Retrograde amnesia was specific to episodic memory but semantic memory was intact
Other amnesia patients demonstrated that some types of explicit memory could be lost, while others were intact, which led to separation of:
- episodic (loss)
- semantic
Subtypes of explicit memory
motorcycle accident case study
Episodic memory
loss - e.g. he said he never changed a tire when he did and knows how to change a tire
He would confabulate and find some reason why he did not hold episodic memory of changing a tire
He lost narrative of his life for more recent events (few years)
He couldn’t imagine what he may be doing in the future or imagining him doing something (episodic prediction)
Impairments to memory impaired ability to simulate a future
Subtypes of explicit memory
motorcycle accident case study
Semantic memory
facts and knowledge- preserved - e.g. he would remember step by step how to change a tire
Memory is not unitary construct
Memory is a variety of different process that are for storing information to be used at a later time
Conscious side: effortful -> explicit/declarative memories
Governed by hippocampus and temporal lobe and the extent of simulation in the frontal lobes
A cellular basis for memory: Long-term potentiation (LTP)
Performed in rats - electrophysiological model
(with electrode intracellular and extracellular to measure PSPs)
Weak stimulus - electrode to provide a signal to induce AP and NT release
The NT will release onto cell of interest where the intra + extracellular electrodes are
Time = 0 -> weak stimulus everything before is baseline level of activity
Cause weak release of NT onto dendrites of cell of interest
Repeating mild stimulation many times
Artificial strong stimulus (tetanus), but likely mimics natural pattern
time = 0 -> moments later, go back to weakly stimulating
After the strong stimulation, the cell has larger EPSPs than usual
The same amount of NT are released but is causing a stronger effect on our dendrites
This experiment was trying to mimic the conditions where long memories are formed
Memory is the strengthening of connections (synapse) between neurons - changes in how the synapse looks and functions
How LTP works
AMPARs - glutamate receptor (ligand gated ionotropic channels) - Na+ enters cell when channel opens and causes depolarization of the cell
NMDARs - glutamate receptor (ligand gated ionotropic channels)
They have a binding site for magnesium
under quiet conditions, not much is happening because magnesium is blocking the NMDAR
When glutamate binds, the channel opens up but no ions can pass through
Under high activity conditions (whenever memory forms), lots of depolarization -> inside of cell becomes more positive and repulses the magnesium ion and pushes Mg out of receptor
When glutamate binds, the channel opens and positive ions will enter the cell (excitatory) and depolarize the neuron
They let in Na+ and Ca2+ -> changes size of EPSP
There is a lot more Ca2+ outside cell -> concentration gradient favours entering the cell
Ca2+ is a potent signalling molecule -> signals for changes in cell
2 types of changes:
Immediate functional changes
Long term potentiation (LTP) - slower
Changes during LTP
Functional
(immediate)
Ca2+ adds more AMPA receptors to the membrane - more likely for NT to bind when there are more receptors -> stronger EPSP
Changes during LTP
Structural
gene
(slower, long-lasting)
Synapse physically gets bigger and the dendritic spines can enlarge and grow
Changes in gene expression - need proteins to be expressed and the cytoskeleton to change
Changes during LTP
Functional (immediate)
Structural (slower, long-lasting)
Ultimately, change in sensitivity of synapses
NMDARs are implicated in a number of brain dysfunctions
LTP is more prominent in memory-related areas + epilepsy
There are a lot of NMDAR in areas related to memory- e.g. medial temporal lobe - hippocampus and surrounding cortex
Far less LTP in other areas of brain - e.g. occipital lobe (vision)
These areas are where epileptic focus is more likely to be - This LTP process may be part of what is dysfunction for people with epilepsy
NMDARs are implicated in a number of brain dysfunctions
NMDAR activity allows Ca++ into the cell
Ca++ is a potent signalling molecule
Too much Ca++ triggers apoptosis (seen when there is too much activity)
As in stroke penumbra
As in excitotoxicity (too much glutamate and NMDARs)
As in tonic-clonic seizures (can lead brain to be hypoxic and may induce apoptosis)
NMDARs are implicated in a number of brain dysfunctions
Alcohol, PCP, ketamine are NMDAR
Alcohol, PCP, ketamine are NMDAR antagonists
Negative Effect on memory retention
Korsakoff’s syndrome
Aka Wernicke-Korsakoff’s syndrome
It is a type of anterograde amnesia often dementia (can have cognitive and behavioural impacts)
It is not caused by dysfunction due to the medial temporal lobe
A medial diencephalic (thalamus/hypothalamus) amnesia
Caused by brain damage due to thiamine (vitamin B1) deficiency (more common)
Severe anterograde amnesia, mild retrograde amnesia
Commonly seen in prolonged, heavy alcohol consumption -> leads to severe thiamine deficiency
Korsakoff’s syndrome
A medial diencephalic (thalamus/hypothalamus) amnesia
Damage especially to medial thalamus
C.f. Patient NA - fencing and the the sword went through the mask, through his nose and pierced his brain
Damage to medial thalamus left this individual with a profound amnesia
Korsakoff’s syndrome
Commonly seen in prolonged, heavy alcohol consumption
leads to severe thiamine deficiency
Alcohol is a thiamine transporter blocker - reducing the amount of thiamine we are able to absorb into brain
Heavy drinkers get a lot of their caloric intake form alcohol and do not eat enough to get their nutrients
Profound anterograde Amnesia + some mild retrograde amnesia (most recent memories) + sensorimotor problems, confusion, personality changes (i.e. dementia)
Often more cognitive impairments when vit B deficiency brain damage is due to alcohol whereas when the vit B deficiency is not due to alcohol, cognition is mostly intact
Can slow down the progression of korsakoff’s syndrome by giving thiamine (vit B) but can never reverse the effects
eficiency
Proposed neural circuit for explicit memory
Medial temporal lobe (hippocampus and surrounding cortex) is a big part of memory formation
Prefrontal cortex - plays big role probably due to big role in working memory
Medial thalamus: Mediator of sensory info to many structures - corticothalamic loops
plays a big role in circuits for explicit memory
Brainstem to cortical systems + sensory and motor info + rest of isocortex => these are all of the conceptual and sensory processing which brings info for the Medial temporal lobe + PFC + medial thalamus to form memories
Damage to medial thalamus
Even though the hippocampus is left intact, PFC and medial temporal lobe cannot function normally without inputs from the medial thalamus to lay down memory
Working memory and older memories are intact
Ability to form new memories has been damaged to the medial thalamus
Alzheimer’s disease
Most common cause of dementia
As life expectancy gets longer, the prevalence of AD gets higher
AD is related to age related decline
Early symptoms sometimes referred to as mild cognitive impairment (MCI)
~13% of the people over the age of 65 have some of the symptoms of AD
Appears first in the medial temporal lobe structures, then to cortex -> related to early symptoms of selective memory decline - loss of explicit memory
No cure and is fatal
Diagnosis traditionally “probable” until post-mortem
Must slice the brain to find evidence of AD
Recently getting biomarkers and imaging that are changing this
Alzheimer’s disease
Early symptoms
selective declines in memory - e.g. failure to find the specific words you are looking for
Alzheimer’s disease
Later symptoms
confusion, irritability, anxiety, deterioration of speech - e.g. suddenly not knowing where they are or where they parked the car, which can be anxiety provoking, not knowing what year it is or who they are talking to
Alzheimer’s disease
Advanced stages
+ genetics
difficulties with even simple responses or behaviours (e.g. swallowing, bladder control)
Tremendous incidence in older adults
Occasional early onset from genetics, but otherwise no single gene associated with AD
There is a genetic component involved - simple type of gene transmission from one family to another => early onset type (but makes up only ~5% of all cases), where symptoms arrive as early as 40s
If you have an immediate family member with AD, you have a 50% chance or better of having AD
The defining characteristic changes of AD (3)
- Brain volume decrease
- Neurofibrillary tangles
- Amyloid plaques
Brain volume decrease
massive loss of brain tissue and loss of synapses
By losing synapses, lose memories
Eventually the neurons start to die
Ventricles enlarges as brian fills reducing brain size in skull with CSF
Neurofibrillary tangles
I.e. Hyperphosporylated tau aggregates Intracellular
Tau important for maintaining cytoskeleton’s integrity
When tau becomes hyperphosphorylated, it will start to aggregate and clump with itself
Intracellular processes
Cannot say this is causing AD but definitely a defining a characteristic
Amyloid plaques
Comprised of beta-amyloid protein, aka A-beta
Beta-amyloid comes from amyloid precursor protein (APP), which is cleaved to make beta-amyloid
Present in healthy and AD brains
Plays a normal function neurons - may be related to changing the structure and function of synapses => synaptic plasticity
May play a role in stress and inflammation but not well understood
Areas where there are lots of changes Synapses and where there are lots of LTP will be damaged first
Aggregation of the amyloid plaques showing earliest in the medial temporal lobe + amygdala
Do not know whether it is the cause or product of AD
Extracellular
Time course of AD
Likely the end result of processes long progressing in silence
Amyloid plaques show up earliest - when neuronal integrity starts to decline
But many people with higher A-beta levels have no changes to their cognition
Tau tangled slow up later - tau tangles may be a byproduct of the disease and the brain damage
Suspected that AD is going on for years prior to being symptomatic
Seen with MS and PD
Biomarkers for AD
(a combination of these factors could indicate someone may have AD)
1. Low beta-amyloid levels in cerebrospinal fluid
2. High tau levels in cerebrospinal fluid
3. PET imaging of beta-amyloid levels (e.g. Amyvid)
4. PET imaging of tau/hyperphosphorylated tau
Pilot phase
5. Decreases in hippocampal volume (MRI) - major biomarker for AD
Structural imaging of brian volume to measure the reduction in brain size
6. Decreases in brain metabolism (FDG-PET)
7. Body weight