Final Flashcards
1
Q
Epilepsy
A
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
2
Q
Seizure
A
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
3
Q
Preictal
A
prior activity seen before a seizure; may give some sort of cues that the seizure is coming
4
Q
Ictal
A
seizure itself
5
Q
Interictal
A
time between seizures
Interictal pattern often has distinct patterns that emerge in EEG
Any seizure over 5 minutes -> need intervention
6
Q
Despite “unprovoked” in the definition,evidence suggests it might be otherwise
A
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
7
Q
Epilepsy is common
A
(~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)
8
Q
anticonvulsant (anti-seizure) drugs
A
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
9
Q
Seizure vs. convulsion
A
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
10
Q
Stigma is extremely common with epilepsy
A
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
11
Q
Epileptic aura
A
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
12
Q
Epileptic aura
2 important reasons
A
- 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
13
Q
Focal seizure
A
does not involve the entire brain. Usually localized to a single brain area - focal single brain area
- Simple partial seizure
- Complex partial seizure
14
Q
Complex partial seizure
A
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
15
Q
Simple partial seizure
A
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
16
Q
Generalized seizure
A
involves the entire brain of synchronised brain activity
- Absence seizure
- Tonic-clonic seizure
17
Q
Tonic-clonic seizure
A
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
18
Q
Absence seizure
A
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
19
Q
Secondary generalization
A
when a focal seizure evolves into a generalized seizure
Most seizures start at a focus but strong intense activity will spread out
20
Q
What to do if someone is having a seizure?
A
Do not walk away
Comfort calmly
21
Q
What to do if someone is having a seizure with convulsions?
A
Never touch them Ease person to the floor Clear area around them - soft around head Start timer - under 5 mins okay loosen anything tight
22
Q
General risk factors Epilepsy
A
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
23
Q
Seizures and head injury
A
(~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
24
Q
Comorbidities
People with epilepsy are more likely to experience the following co-existing medical conditions:
A
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
25
Common treatments for epilepsy
1. Anticonvulsants
2. Vagus nerve stimulation
3. Ketogenic diet
4. Cannabidiol (CBD)
26
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
27
Anticonvulsants
| Four categories of side effects
1. Problems with motor speed, cognitive speed - physically and mentally slower
2. Impairments to memory
3. Problems with mood
4. In some cases the development of psychosis- emergence of positive symptoms: delusions, hallucination, disorganised thought, speech and behaviour
5. For severe intractable epilepsy, surgical procedures are sometimes required
No brain is better than bad brain
28
Vagus nerve stimulation
both sensory and motor
| Statistically minor benefits but no idea why they are beneficial
29
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
30
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
31
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
32
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
33
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
34
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
35
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
36
Memory duration
| Long-term memory
HM could not consolidate
| He had long term memory but lost the ability to transfer memory to long term
37
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
38
Consciousness & memory
| HM
HM’s memory was not impaired for: -> these memories are outside of hippocampal processes
39
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
40
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
41
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
42
Explicit memory
memory in our conscious awareness that can be recalled
| E.g. remembering what you ate or wore
43
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)
44
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
45
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
46
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
47
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
48
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
49
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
50
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
51
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
52
Changes during LTP
Functional (immediate)
Structural (slower, long-lasting)
Ultimately, change in sensitivity of synapses
53
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
54
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)
55
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
56
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
57
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
58
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
59
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
60
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
61
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
62
Alzheimer’s disease
| Early symptoms
selective declines in memory - e.g. failure to find the specific words you are looking for
63
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
64
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
65
The defining characteristic changes of AD (3)
1. Brain volume decrease
2. Neurofibrillary tangles
3. Amyloid plaques
66
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
67
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
68
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
69
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
70
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
71
Biomarkers for AD
| Low beta-amyloid levels in cerebrospinal fluid
CSF can be measured from spinal cord
Reason suspected: beta amyloid is aggregating in their brain which is why we see less of it in the CSF
Relationship between sleep and beta amyloid removal from the brain -> sleep disruption is related to alzheimer's disease which may be explain why Beta-amyloid is aggregating brain and not leaving
72
Biomarkers for AD
| High tau levels in cerebrospinal fluid
Total tissue damage causes more tau to be released - more intracellular process
As cells are dying, the amount of tau that is around should be higher
73
Biomarkers for AD
| PET imaging of beta-amyloid levels (e.g. Amyvid)
Creating ligand that is going to bind to protein beta-amyloid -> can visualise if these aggregations are occurring at a higher than usual rate
74
Biomarkers for AD
| Decreases in brain metabolism (FDG-PET)
Changes in brain activity (glucose PET scan - given radioactive glucose)
Overall brain metabolism in patients with AD drops off and decreases
75
Biomarkers for AD
| Bodyweight
One of the earliest indicators of AD s reductions in body weight
Occurs even before clinical symptoms of dementia
76
Theories of pathogenesis of AD
1. Amyloid cascade hypothesis
2. Neurofibrillary (or tau) hypothesis
3. Vascular hypothesis
4. Pathogenic spread hypothesis
5. Gum disease?
77
Amyloid cascade hypothesis
| down syndrome
Idea is that amyloid is causing all the other problems (loss of synapses, cells, decrease brain size, and symptoms, etc)
Amyloid develops earliest and occurs in the medial temporal lobe
In individuals with down syndrome (developmental disorder) - they have a third copy of chromosome 21
Matters because the amyloid precursor protein (APP) gene is on chromosome 21
Individuals with down syndrome have extra production of beta amyloid protein
In individuals who live longer lifespans and have down syndrome -> 100% of them will develop amyloid plaques
Not all will develop AD but around 60-80% will
Some individuals who do not have downs syndrome have an extra chromosome 21 or parts of the chromosome 21
They found that up to 15% of neurons had an extra chromosome 21 researchers looked at for post mortem studies on AD
Leading to an overproduction of beta-amyloid
78
Neurofibrillary (or tau) hypothesis + limitations
Idea is that tau is the main cause of AD
limitation:
But they show up later in AD
Mutation of tau in animal models - mutation of tau will cause the build up of the tau tangles but does not cause any A-beta plaques
79
Vascular hypothesis + limitations
Idea is that problems with blood flow is playing a major role in AD
Many individuals who cause vascular insults to themselves (e.g. smoking) has a higher likelihood of developing AD
AD patients have less blood flow to brain in general which is correlating with the rate of their cognitive decline - mild correlation
Limation:
Does not tell the mechanism of why AD is happening
Mild correlation
80
Pathogenic spread hypothesis
Idea that there is a chain reaction from a misfolded protein that clumps together with a healthy protein and causes that to misfold and causes a chain reaction of misfolding
Complementary to amyloid cascade hypothesis
81
Gum disease
Coming from private research
People with gum disease had a much higher chance of developing AD
70% higher risk of developing AD if you had gum disease
the bacteria from it - produces some toxic protein
They did some tests where they increased the level of bacteria in these animals and found that the bacteria can migrate from the mouth to the brain
The toxic protein increases production of A-beta
microbial infections in general - may be driving the production of A-beta and inflammation leading to AD
82
Amyloid cascade hypothesis
| limitations
Beta-amyloid is part of normal brains
There are some individuals with a-beta plaques with no symptoms of dementia
Up to ⅓ of people who did not have AD had moderate to high levels of amyloid plaques but they do not have any symptoms of AD
Many people believe this discrepancy is due to inflammation and inflammatory responses
These people who do not show symptoms of AD with A-beta do not show an inflammatory response to AD whereas individuals with AD have the inflammatory response
The amount to A-beta someone has does not correlated with the severity of dementia or amount of neurodegeneration
Animal model with mutation with B-amyloid processing, it will create A-beta plaque and tau tangles
83
Treatments for AD
1. Cholinergic (ACh) agonists, e.g. acetylcholinesterase inhibitors - blocking enzyme that breaks down acetylcholine
2. NMDAR antagonist (memantine)
3. Lithium
4. Physical exercise especially cardio, environment enrichment
5. Even coffee/caffeine
6. Education - environment enrichment
84
Cholinergic (ACh) agonists, e.g. acetylcholinesterase inhibitors - blocking enzyme that breaks down acetylcholine
Treatments for AD
Early efforts to treat AD are based on the observation of changes in Acetylcholine functioning early in AD - though it was a problem with acetylcholine function
People started to find ways to increase acetylcholine function -> these drugs are still regularly prescribed (cholinergic agonist)
They are ineffective and have side effects
85
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NMDAR antagonist (memantine)
Treatments for AD
```
Glutamate receptor antagonist
Seen some effect on deterioration -> maybe reduction in excitation is supposed to reduce A-beta (important part of synaptic plasticity)
86
Lithium
| Treatments for AD
Commonly prescribed in BPD but no idea what it does in AD or BPD
Improves mild cognitive impairment
87
Physical exercise especially cardio, environment enrichment
| Treatments for AD
Also seem to be preventative - modest neuroprotective effects
Reduce likelihood of age related cognitive decline
Major benefit from cardiovascular exercise
Improve cognitive capabilities for a longer time
88
Even coffee/caffeine
| Treatments for AD
Modest neuroprotective effects
| Reduce likelihood of age related cognitive decline
89
Education - environment enrichment
| Treatments for AD
Delays onset of cognitive decline
| Reduces likelihood of AD
90
Emotion
a subjective, conscious experience that is characterised primarily by psychological expressions, biological reactions, and mental states
Emotions influence how we act (behaviour and interacting with the world); moods influence how we perceive the world
91
Long history of emotions supposedly clouding judgement
Loss of function experiment by lesion of emotion producing regions cause judgement impairment outcomes
92
Emotions vs. logic, emotions vs. reason, emotions as irrational (decision that benefits organism)
Emotions are be valuable in guiding our rationality
| But emotions play a big role in our decision making machinery
93
Darwins, James: emotions selected for not against
Emotions are seen all throughout mammalian lineage -> evolutionary fitness benefit from emotions
Perhaps that evolutionary benefit was applicable before but not now in term so of evolution
When emotional systems are damaged, there are detrimental effects on our behaviour
94
Emotion were considered separate from cognition for a long time
Most of 20th c: understudied due to emphasis and focus in cognition and behaviour
Many studies that did start to look at emotions were from classical and operant conditioning perspectives for emotions
95
Anecdotally: Mr. Spock or Phinease Gage
Mr. spock from star trek is supposed to be an individual who is very smart because he can turn off his emotions and think and make decisions logically -> but we see that without emotion, decision-making is greatly impaired
Central thesis: emotion is critically linked to value -> disruptions that impair emotion also impair judgement and decision making
96
Misconceptions
| Hemisphere model -> left/right brain people (myth)
Right hemisphere model -> the right hemisphere is specialised for all aspects of emotional processing
While the left half of the brain is related to language and linguistic functions
Valence Model -> right hemisphere is responsible for processing negative emotions whereas the left brain is responsible for processing positive emotions
97
Meta-analyses for Dysfunction affecting emotion, stress, and decision-making
left brain and valence model
large body of studies (analysis of many analyses) on the theories above
the truth is more complicated; Both models above are too general for an anatomical fit
No major difference in emotional processes of either side of the brain
In certain individual structures such as the PFC and amygdala, there may be individual lateralization but does not line up with valence model; merely that one side of the amygdala may be more strongly activated than the other for a certain task
98
Dimensions of emotion
| Some (e.g. paul ekman) argue for discrete emotions
Categorical approach to emotions
Linked emotional faces to so called primary emotions
He argued that it was universal that all cultures understood anger and other emotions
We build our more complicated emotions out a combination of more simpler emotions
Not much support
99
Dimensions of emotion
| Others suggest emotions are comprised of dimensions (e.g. valence (+ or -) and intensity)
If you map any one of the subjective state in our mind, the emotion has a particular combination of valence and intensity to them
Tied to behaviour with the value: These dimensions are thought to guide perception and action (e.g. approach/avoid)
Positive valence -> things we approach
Negative valence -> things we avoid
But the truth is, we approach things that are negative too (e.g. frustration is motivating, some people like sad or scary things)
Ambivalence - things that feel positive and negative that the same time
100
Regions of emotion
PFC, amygdala, cingulate cortex, hippocampus, thalamus, hypothalamus, mammillary bodies
Single emotion does not map onto single area and many regions are associated with emotion
Diffuse sets of regions that are involved in the experience of emotion
Many emotional regions overlapping from one state to another yet distinct
E.g. happiness and sadness activates similar areas
Many, big areas (e.g. the PFC)
Often not 1:1 for function: cell
(i.e population coding- one neuron cannot tell you enough information, need a population of neurons in order to have this experience)
A cell cannot be a sad cell but is involved in a variety of different experiences
Emotion is playing a role in perception and memory as the regions overlap
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Klüver-Bucy Syndrome
emerges when an animal specifically when an animal’s anterior temporal lobe has been removed commonly done in nonhuman primates
Typically primates are afraid of a lot of things: snakes, humans, etc
When the anterior temporal lobe is removed, they are happy to interact with snakes and inspect humans - lack of fear
These animals also tended to be hyperoral (investigate many things with their mouths) which may be because some of their visual regions have been damaged
Repeatedly investigating familiar objects
Misdirected hypersexuality: These animals also had an intense indiscriminate hypersexuality towards animals and inanimate objects
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Amygdala
in anterior temporal lobe that is related to the expression of fear or fear related behaviours
Not the only part involved in fear and amygdala is involved in a variety of other behaviours, cognitions, learning, etc
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Patient SM
the woman with contained bilateral damage to amygdala (urbacvic disease - causes specific lesion by calcification) experienced no fear
She is incapable of experiencing fear subjectively, physiologically, behaviourally
Remarkably poor job of identifying scared faces and some other faces
They showed her a series of scary movies and noticed she basically had no fear for any of them compared to controls
Researchers have exposed her to normally scary situations -> she will respond with interest, curiosity, or excitement but no sense of fear
SM has been exposed to a variety of unfortunate situations in her life -> she’s been robbed at gunpoint and knifepoint multiple times, a number of domestic situations
She is incapable of judging the trustworthiness of a face and dangerous situations
Lack of fear has led her into unnecessarily dangerous situations
She has no sense of personal space but understands that others need it
Patient SM: CO2 exposure -> feeling of suffocation -> patient SM felt an intense sense of panic/fear for the first time and removed the helmet
Subjective experiences of fear will be manifested in the cortex
Amygdala is important for the learning of the fear and a variety of learning
Fear keeps us safe and out of potentially dangerous situations that optimise our well-being over the long term
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Amygdala and learning
| Primate/rodent electrophysiology
Roughly equal numbers of amygdala cells that respond to appetitive versus aversive stimuli
Some cells respond for both appetitive versus aversive stimuli (i.e. suggesting that it fires for arousal, not valence)
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Amygdala and learning
| Often implicated in updating value
E.g. During stimulus de-valuation (satiation)
| Sensory specific satiety goes is dysfunctional with amygdala damage
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Amygdala and learning
| Appetitive versus aversive values
Fear learning learning happens very fast as compared to appetitive learning
Small punishment has the same value large reward
Punishment/aversive effects has a disproportionately strong effects on the brain
Makes interpretation difficult - amygdala is not just involved in fear but is clearly involved in learning between stimulus and value
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Phineas gage: brain dysfunction and recovery
Ventromedial prefrontal cortex (ventral surface to the medial wall) -> where phineas gage’s brain was damaged
vmPFC more on emotional regulation, social appropriateness, and other executive function
Orbito prefrontal cortex: cortex directly behind your eyes
Likely unilateral damage after computer simulations of how the iron rod may have shot through his head
But executive dysfunction can happen from a variety of PFC damage
Phineas’s family and friends noticed:
Before: capable, efficient, sharp, energetic and persistent at executing his plans
After: fitful, indulgent, impatient of restraint or advice when when it conflicts with desires, arranging plans then abandoning
change in personality
Ability to speak and count were all in tact
He worked at a carnival after which may suggest he had an adaptive response to his situation and made money out of the situation as he could not work for the railway anymore
He maintained a job as a horse-carriage driver in Chile - became estranged from his family
A lot of planning and unforeseen circumstances - challenging for people with PFC damage
Perhaps due to repetitive nature of job
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Good example of recovery and similar to contemporary patients
Phineas gage: brain dysfunction and recovery
Restitution of function: finding new habit, skills, and functions that could compensate for the loss of the brain tissue
Other patients with prefrontal cortex damage often have dramatic changes in their personality but often with a variety of skills and tricks and habits, they can compensate their lost capacities
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Prefrontal lobotomy
Becky the chimpanzee was performing complicated cognitive task and displayed frustration when she could not complete task accurately
When they damaged the frontal cortex, becky did not display any frustration behaviour when she could not complete task properly
The idea was to help humans who were disruptive -> many of the participants were not consenting adults, including children, prisoners, or women
Deliberately squishing and damaging part of the prefrontal cortex with pick through the eye
These prefrontal lobotomies are not beneficial in any way but they can be quite harmful but too late -> ~40,000 americans got a prefrontal lobotomy
Effects on an individual varied drastically
Effects on life varied drastically from incapacitation to recovery
Some people had problems with emotional regulation, motivation
Some people had major disabilities in get up and go behaviour
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the PFC & “executive functions”
(variety of cognitive skills and abilities that allows us to switch from being an organism that reacts to the environment to an organism that reflects and plans for the future)
- Planning, Organisation, Flexible thinking, Monitoring performance, Multi-tasking, Solving unusual problems, Self-awareness, Learning rules /social rules, Social behaviour, Decision making, Motivation, Initiating appropriate behaviour, Inhibiting inappropriate behaviour, Regulating emotions and, experience of emotion, Concentrating
Patterns of activity not just in cognition but meta cognition (thinking about thinking- monitoring own thoughts), juggling of cognitive demands cognitive nuanced sophistication (decision-making performance monitoring- rules and norms)
Executive functions are not all of our higher cognitive functions or conscious perception of individuals, and not alot of our top-down attentional areas, and does not encompass our ability to talk or walk
The prefrontal cortex is not homogeneous function (sometimes divided up as dorsolateral and ventromedial prefrontal cortex)
Subregions of the prefrontal cortex is contributing slightly different things
Dorsolateral PFC is an essential part of these executive functions
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Executive dysfunction: bilateral vmPFC damage
vmPFC (OFC) damage
Ventromedial prefrontal cortex (ventral surface to the medial wall) -> where phineas gage’s brain was damaged
vmPFC more on emotional regulation, social appropriateness, and other executive function
Orbito prefrontal cortex: cortex directly behind your eyes
But executive dysfunction can happen from a variety of PFC damage
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Commonly studied: bilateral PFC damage, as it’s more commonly observed in patients
Most intellectual ability preserved -> able to perform working memory tasks, no linguistic impairments, no impairments in ability to do maths or move around
Changes in personality emerge with some people more severe than others
Inappropriate around people
Problems with prioritisation (e.g. lost in the filing cabinet at work with person with brain tumour) - can no longer identify what you should be focusing on
Emotional dysregulation
Repeat mistakes almost on purpose despite often “knowing” it’s suboptimal
Loss of “get up and go” - problems with motivation
Problems with cognitive flexibility
Problems thinking ahead or sequencing steps for a task
Rigidity in thoughts and actions
People normally change their behaviour/strategy to be more successful at a task but people with PFC damage are not easily flexible with their thoughts or actions
Problems with attention and concentration
In many cases people have anosognosia
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PFC damage anosognosia
they do not know that their behaviour is inappropriate or that their executive functions have been compromised
They do not recognize change in their behaviour and thoughts because the part of the brain that recognizes changes is in part the PFC
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Unilateral vmPFC damage
| Right Side vmPFC damage
```
Use overlay (overlapping structural MRI) method- more sophisticated way of looking at lesion damage shows clear picture of role between left vs. right vmPFC
Disturbances just described
I.e. Executive dysfunction: impairments in planning, motivation, emotional regulation, social inhibitions
```
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Unilateral vmPFC damage
| left Side vmPFC damage
Use overlay (overlapping structural MRI) method- more sophisticated way of looking at lesion damage shows clear picture of role between left vs. right vmPFC
Far fewer impairments compared to right or bilateral vmPFC damage
Typical social and interpersonal behaviour
Stable employment
Unchanged personality (for the most part)
Decision making ability relatively intact
E.g. phineas gage brain damage was much more left vmPFC which may explain why over the lifespan, he did relatively well and recovered well
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Stress
Can be significant life events (e.g. death of a loved one, marriage)
But also “the daily grind”, lives of “quiet desperation”
Can be active or passive, short-term or long-term
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Stress Can be active or passive, short-term or long-term
Active stress: e.g. holding an animal restrained, pinching tail, social defeat
Passive stress: e.g. Maternal neglect/separation, social isolation, environment or sensory deprivation
Active and passive stress is relatively similar in the brain
Short term: Stress is adaptive by design - short term stress is good
Long term stress: we are not designed to live under chronic stress (detrimental effects)
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Stress immunization
i.e. if you have previously been exposed to controllable stressors upon which you have some sense of control -> makes you less susceptible (more resilient) to stress effects later on
Even if you can or cannot control the new stresses, if you have been previously exposed to controllable stresses, you will have a stress immunization response, less exaggerated stress response
The way we respond to stress is directly related to our previous exposure to stress
BUT if you have previously been exposed to uncontrollable stresses, you will become hypersensitive to stresses whether it is controllable or not
Stress learning that happens in childhood influences how we respond to stress in adulthood
Stress immunization or lack thereof is most pronounced in childhood but also seen to a lesser degree during adulthood
As an adult, exposure to those controllable stressors make you more resilient to those later stressors
E.g. exam can control the amount of preparedness
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Dual stress pathway
Sympathetic response: Immediate effects sent by APs are driven by epinephrine and norepinephrine (both work as hormones and neurotransmitters, outside the CNS in the sympathetic NS) which is secreted by the adrenal gland (e.g. causes heart to race)
HPA axis: slower and longer lasting, hormonally driven (HPA: hypothalamus - pituitary - adrenal) - cortisol (corticosteroids) releasing pathway
Releasing energy and getting body ready to deal with stressful situations
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Acute stress
has some drawbacks, but is generally beneficial for us
Stress is an adaptive response to threat
When stress levels are mild, there are benefits all across the board
Even improves immune system
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When stress levels are mild, on stroop test and morris water maze
there are benefits all across the board
E.g. stroop test which requires behavioural flexibility is improved with acute stress
E.g. acute stress improves performance on virtual morris water maze
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Acute stress benefits
implicit memory (switching to more basal ganglia sets of behaviour), simple tasks, habitual and well-rehearsed tasks/skills
If something is not well - rehearsed or not a habit, it is going to suffer under high stress situations
Anything that requires PFC contributions, there are impairments in performance
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Acute stress costs
cognitive flexibility (e.g. stroop task), working memory, executive functions (juggling or micromanaging a few things, monitoring own performance, selecting from a series of actions that are appropriate for a given context)
Explicit memory is poorer under high stress conditions
PFC becomes quieter
E.g. if you put a high performance athlete in front of 20,000 people, they perform better because the skills are extremely well-learned to them
E.g. exam: if you are well-prepared, you will perform better on the exam
Getting stuck on a test: difference between pretty well-learned to extremely well-learned
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Chronic stress is real bad
These executive functions are compromised by stress, especially chronic stress conditions
Compromises immune functioning over the long term
Acute stress has mild benefits
Compromises mental health
Depression and anxiety is a major correlate to chronic stress
Reduces hippocampal volume under chronic stress - just a reduction in dendritic branching and synapses not the death of cells
Seen in lots of studies of depression and some in anxiety
The hippocampal cells are probably still there
Increases PFC catecholamines (monoamine NT specifically NE (norepinephrine), DA), decreases PFC function, decreases PFC dendritic spines
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Yerkes-dodson curve related to stress
| low, moderate, high levels of stress/arousal
Increases PFC catecholamines (monoamine NT specifically NE (norepinephrine), DA), decreases PFC function, decreases PFC dendritic spines
Effect on PFC is not linear Yerkes-dodson curve
Low levels of stress or arousal (and catecholamine release): drowsy or bored, relatively little activity in PFC and not tuned activity
Moderate levels of stress or arousal (and catecholamine release): more activity in PFC, more networks are present, neurons are tuned towards specific stimuli -> optimal PFC functioning (alert)
High levels of stress or arousal (and catecholamine release): feel stressed, and PFC become quiet, and executive functions are impaired, resorts to lower level functions
In the short term, this is an adaptive function as our habits and well learned tasks come to the forefront, deeper brain structures can take over
Many regions in the PFC, they work interconnectedly with our internal and external environment and our behaviours
The way in which they fire and respond to things are not static -it is a function of over level of arousal/stress
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chronic stress on behaviour
Reduces performance on hippocampal- or PFC-dependent tasks
On hippocampal based tasks like spatial learning, navigation, other long term memory based tasks - there are impairments under chronic stress conditions
Impairs decision making
Thinks about now and impairs ability to plan forward
Behavioural observations in high stress conditions:
Stress impairs working memory, attention (sort of), planning, etc.
BUT stress improves habitual behaviour
We also see PFC inhibition and amygdala/basal ganglia/HTh activation
People who are living with PFC damage are not that different from people living in chronic stress conditions
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The chronic stress of poverty
| An implication of modern society: people are poor because they are bad decision makers
People’s SES are related to the quality of decisions they make
Being poor is not the result of poor decision making, but bad decision making can emerge from being poor
Decisions that are more focused on immediate goals
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The chronic stress of poverty
| A study in New Jersey reminded low SES to of poor individuals with car payment scenario and did cognitive tasks
The financial blow reduces cognitive capabilities in those of lower SES
When the lost of car repair was not expensive, there was no decrease in spatial and reasoning tasks
High SES individuals performed fine in both conditions - they were no better than the low SES individuals when car repair condition was cheap
Thinking about their bills and scarcity is an impediment on their cognitive tasks
BUT Poverty, in and of itself, reduces IQ by ~13 points
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The chronic stress of poverty
| A study on farmers pre and post harvest on cognitive tasks
Following the harvest when resources were abundant, the financial penalty did not impair their cognitive tasks
Pre harvest, they performed worse on cognitive tasks
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The chronic stress of poverty
| Exposure to irregular reward intervals guides even individuals with high baseline self-control to act impulsively
Exposure to irregular reward intervals guides even individuals with high baseline self-control to act impulsively
Asking children to wait for their marshmallow is often a measure of self control
The marshmallow task overlaps substantially with SES -> great predictor
Under some economic level, it is smart to eat the marshmallow now -> it is faulty reasoning to always wait for the second marshmallow
Especially when there is inconsistency in when the monetary rewards are given, they can make people who are often good decision makers into impulsive
Through this inconsistency fo rewards, you can shape the way in which people think and make decisions
Poverty affects executive functions and cost/benefit decision making
Poverty disproportionately affects children and their brains
Poverty affects the total volume of brain
Low SES causes the grey matter in their brain to be smaller than other children as they grow up even though their brains all start at the same size
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To reframe: poverty is chronic exposure to uncontrollable stress -> effect on the brain?
“The evidence indicates that poverty causes stress and negative affective states which in turn may lead to short-sighted and risk-averse decision-making, possibly by limiting attention and favouring habitual behaviours at the expense of goal-directed ones.”
Shifting from executive function driven by long term goals to dealing with the short term and the immediate when the PFC is quieter and the basal ganglia, HTh, and amygdala can take over more functions
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Animal models for chronic stress studies
| In rats, induce chronic stress by separating the rat from mother (maternal separation)
Changes in behaviour and decision-making
Can eliminate many of the effects of maternal separation by running a wet paintbrush over the rat babies heads multiple times a day (simulating mother licking)
Chronic stress indicators are diminished -> remove stress phenotype
we say resign the phenotype
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Animal models for chronic stress studies
| For humans
we say social policies (must be changed in order to mitigate the effects of chronic stress)
Ways of mitigating levels of stress whether changing poverty or increasing social connections, removing isolation
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Studies on fairness in non-human animals
Functional utility of anger: why do we have anger and what benefit does anger give us?
The monkey got angry because the 2 monkeys were paid unequally (one given cucumber and one given grapes for the same task)
Monkey is willing to throw away its cucumber to show its anger to encourage a change in researchers behaviour to receive a grape instead
Anger is not about aggression but about encouraging fairness
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The ultimatum game
2 players: Proposer (1) and Responder (2)
The proposer is asked to split up money however they see fit for how much goes to themselves and how much goes to the other player
The responder can simply accept the offer or reject the offer
If they reject the offer, neither of the players get any money
Economical perspective
The rational thing for the proposer to do is take the maximal amount of money they can and give the other person as little as possible
The responder to accept every single offer because any amount of money is better than nothing at all
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The ultimatum game
| Results
When it's a fair split, everyone accepts the split
But as the split becomes less fair, responders are less likely to accept the split
When receiving $1 as opposed to $9 for the proposer, the responder is rejecting the offer more than 60% of the time
Willing to sacrifice money to punish the other player
Responder rejects the offer because over the long term, we want to tell people that unjust behaviour will not be tolerated -> encourage fairness over the long term
In the long term, encouraging fairness at a cost of receiving nothing will benefit them in the future as well as other interacting with the person
Anger, where you pay a cost to make someone’s behaviour) better guides behaviour toward altruism because you are paying a cost to ensure others benefit from it over the long term
Anger directed at an entity (mostly)
Participants behaviour changes when told they are playing with a computer
As the split becomes more and more unfair the acceptance rate goes slightly down
Participants accept at a much higher rate for the computer than another person because they do not think the computer is badly behaving rather merely an algorithm
Angry behaviour corresponded with SCR (skin conductance response - measures sweating, how open pores are), self report, brain activity
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Activity in the ___ and ____ correlate with reacting offers in the ultimatum game
As the likelihood of rejecting offers get higher, there is higher ___ and ____ activity (more anger)
anterior insula and ACC; insula and ACC
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Frustration
most likely to occur when you are very close to winning but fail at the last minute
Usually, emotions guide us toward beneficial behaviours (i.e. increase out fitness)
E.g. frustration -> supposed to be motivationally invigorating to work harder to achieve near success - signal that we are getting close to success usually
This sense of frustration is manipulated or sometimes used to exploit us
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frustration
| gambling
get the same sense of frustration without actually getting any closer
Slot machine: it may feel subjectively that you are getting closer to success when in reality you are not close to winning
Ideal miss rate to invigorate behaviour the most is somewhere around 30% of the time
we occasionally misapply our emotions (behaviourally speaking)
Near misses feel bad but spur further play especially when you have the illusion of control
Much stronger for after vs. before the payline of slot machine
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slot machine game (induces artificial feeling of frustration) - near miss effect
on brain activity
Anterior insula’s bold levels are correlated with frustration (feeling of almost succeeding/near miss)
ACC activity gets higher in the near miss condition vs. the full miss condition
ACC is tracking performance and how close you were to success
In individuals with pathological gambling disorders, this near miss effect (frustration) in enhanced
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Concluding thoughts on emotions & stress
Emotions are complex in their manifestation and their underlying neurobiological structures
Emotions are clearly linked to value and motivation, and guide our actions
Impairments in emotion impair our ability to navigate the world -> from Dysregulation of the amygdala, HTh, or PFC
Why emotions have different qualities than other cognitions is unclear
Cognitions are uniform and do not have “colour”
Emotions are linked to cognition but they have a quality/”colour” to them
While some emotion categories seem relatively universal, others seem less so
Impairments to emotion impair our ability to successfully navigate our world
Stress is a beneficial adaptation that is maladaptively triggered in contemporary society
While acute stress is beneficial, chronic stress is severely detrimental, especially in its effects on the PFC and hippocampus
Must mitigate chronic stressors to have optimal PFC function
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Pathology
Mental illness - More than an illness
Biological bases, yes -> changes to personality
Socially defined aspects of mental health and mental illness
Evolving -> There is increasing pathologizing of everyday life
Boundaries of mental health are arbitrary
e.g. Schizoaffective disorder
A constellation of symptoms
Polytreatment (giving multiple types of drug) as the norm
People are given treatment that directly targets the symptoms they have and people have many symptoms
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Previously considered mental disorders
Masturbation (19th c.)
Drapetomania -> when black slaves try to escape from their owners
Dysaethesia aethiopica -> laziness
Part of mental illness classification is social
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Are equivalent disorders for schizophrenia found around the world?
To some extent -> these three disorders emerge in almost every culture
e.g. Schizophrenia, bipolar, depression
Some sort of universal biological basis
But there are cultural disparities
The way in which symptoms emerge varies across culture
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“culturally-bound disorders” (manifestation of disorders may differ across culture but the biological basis is universal)
e.g. koro (obsession that a man's penis is going to crawl into his body)
E.g. wendigo (overriding paranoia/worry of wanting to eat human flesh)
E.g. anorexia (not eating - was predominantly seen in affluent western cultures)
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Deinstitutionalization
Previously: sanatorium, asylum, in-patient care -> institutionalisation
People could pay ticket to see mentally ill people in psychiatry facilities like a zoo
Now there is a shift is responsibility and care
People are using medication
higher rates of homelessness, prison
many cases these people have mental health problems and/or addictive substance abuse
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“Balloon theory”
transition form keeping people in institutions to keeping people to higher rates of homelessness and prison incarceration
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Are People With Psychological Disorders Dangerous?
Mental disorders rarely lead to violence and clinical prediction of violence is unreliable
There are a few mental disorders that lead to higher rates of violence
E.g. intermittent explosive disorder, drug addiction especially alcohol, people having delusions to being in imminent danger
Those with mental disorders are disproportionately more often the victims of crime than those non-mentally ill
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Psychosis ≠ Psychopathy
Psychosis is related to positive symptoms of schizophrenia (e.g. loss of touch with reality, hallucinations, delusions)
Psychopathy is a forensic diagnosis
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DSMs
Must be careful deciding on mental disorders as we may be pathologizing on everyday behaviour
DSM-I (1952) and II (1968): psychodynamic-heavy, freud and young
Homosexualaity was a disorder
DSM-III (1980): Spitzer’s vision, exhaustive categorization list
DSM-IV (1994): Conflicts of interest -> more categories and double the length
Many of the authors had ties with pharmaceutical companies
DSM-V (2013): NDAs (authors are unknown), rewrites, a “living document” (online with constant revisions)
The DSM-5 provides an exhaustive classification system for every possible mental disorder.
Gambling emerges into behavioural addiction
Gender identity disorder removed -> instead gender dysphoria
Changes depending on societal changes/understandings
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DSM has several purposes:
1. To guide treatment choices.
Different disorders treated differently although there is some overlap
Schizoaffective disorder: Mood disorders and schizophrenia seem to have some biological interconnectivity
2. To allow clinicians to communicate about same topic
3. To please insurance companies who require a concrete diagnosis
Legitimacy to individuals condition
4. To permit research (via categorization)
People can research similarly
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Schizophrenia: DSM 5 Criteria
2+ of the following, each present for a significant portion of time during a 1- month period (or less if successfully treated). One of which must be (1), (2), or (3) aka positive symptoms of schizophrenia:
Delusions
Hallucinations - commonly auditory
Disorganised speech (e.g., frequent derailment or incoherence)
Grossly disorganised or catatonic behaviour
Negative symptoms (i.e., diminished emotional expression or avolition)
For a significant portion of the time since the onset of the disturbance, level of functioning in one or more major areas, such as work, interpersonal relations, or selfcare, is markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, there is failure to achieve expected level of interpersonal, academic, or occupational functioning)
Aka must be aversive or distressing for individual
Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms
Cannot diagnosis instantly as some drugs can create similar symptoms
During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or by two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
Schizoaffective disorders (bipolar I, depression with mania) have been ruled out
The disturbance is not attributable to the physiological effects of a substance
(e.g., a drug of abuse, a medication) or another medical condition
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What schizophrenia looks like
| Positive symptoms
(hallucinations, delusions, disorganised thought, speech, behaviour)
Drugs that block dopamine functioning can provide benefits/reduce for these symptoms
Commonly manifest in the beginning of the disease
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What schizophrenia looks like
| Negative symptoms
(absence or decrease in emotional expression, motivation, spontaneous speech)
Over time the negative symptoms emerge
Whether or not medication is given or not, these symptoms emerge
Motivation is related to dopamine function
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What schizophrenia looks like
| Cognitive symptoms
(decrease in attention, executive function, working memory) -> perhaps due to decrease in firing in the PFC
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What schizophrenia looks like
| mood symptoms
(showing inappropriate emotions for certain contexts, depression)
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What schizophrenia looks like
Symptom manifestation can be different among different individuals -> difficult to classify
Prevalence: 0.5-1.5%, slightly more common in men
Onset: teens to early 30s
Atypical behaviours even in younger children who will later manifest with schizophrenia (aka there are developmental predispositions for the disease)
Unemployment, poverty, homelessness common
What it doesn’t look like: Dissociative identity disorder (multiple personality disorder) -> patients with this disorder usually have very horrific things happen in their lives
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Who gets schizophrenia/ risk factors
Having a Twin with schizophrenia -> vastly increase chances
Suggests strong genetics and/or biological/developmental component
Closer family members with schizophrenia, the higher risk of schizophrenia
no candidate gene for schizophrenia
Cannabis and psychostimulants =correlation with=> rates of psychosis/schizophrenia by a bit
Living in an urban environment increases risk of developing schizophrenia
Moving from urban to rural environment
Being born in the winter
Mother having some kind of in utero infection, commonly influenza
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Brain changes in schizophrenia
| structural and functional
Gross anatomical change can be seen in schizophrenia
Structural: widespread decreased grey matter, sometimes abnormal white matter patterns, enlarged ventricles
Hippocampus: atypical layering structure, atypical neuronal shape
PFC: fewer dendritic spines on pyramidal neurons and fewer GABAergic interneurons
Suggests developmental issue
Functional: abnormal (often hypoactive -> hypofrontality) frontal and temporal lobes (incl. hippocampus), dysfunctional dopamine neurotransmission (pre- and postsynaptic), probably much more
Take-away: best considered a neurodevelopmental disorder
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Non-pharmacological Treatments
Most valuable in combination with pharmacological treatments
There are few non-pharmacological treatments that are useful during the acute phases of schizophrenia.
Cognitive-behavioural therapy (CBT)
insight therapies
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Cognitive-behavioural therapy (CBT)
Cognitive-behavioural therapy (CBT) (learn and identify patterns of thought and thinking about the world that lead to suboptimal consequences and changing those thoughts) has shown some promise for the management of positive and negative symptoms when combined with pharmacological interventions.
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insight therapies
Various insight therapies as well as counselling can be useful when the individual has been stabilized on medications: Help with any co-existent mood or anxiety disorder, support as they deal with the difficulties of integrating themselves back into society, etc.
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Pharmacological Treatments
| schizophrenia
The most common treatments (for positive symptoms) are pharmacological: anti-psychotic drugs (aka neuroleptics) -> mitigates positive symptoms
There is usually less luck in treating the negative symptoms of schizophrenia
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Discovery of Neuroleptics
a surgeon noticed that the administration of chlorpromazine to his patients to counteract swelling had a calming effect.
He subsequently suggested that it might have a calming effect on difficult-to-handle patients with psychosis.
Subsequent research showed that, after being administered for a period of 2-3 weeks, it alleviated the symptoms of psychosis in many patients
Use if anti-psychotic drugs lead to parkinsonia -> displaying symptoms of parkinson's disease with massive sedative effects in movement
Parkinsonian effects diminish and so does the positive symptoms over time
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Dopamine Theory of Schizophrenia
The theory that schizophrenia is caused by too much activity at receptors for the neurotransmitter dopamine -> overactive dopamine system contributing to schizophrenia
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Dopamine Theory of Schizophrenia
| This theory was based on several findings:
1. The brains of individuals with Parkinson’s disease have marked dopamine depletions; and antipsychotic drugs produce symptoms that are similar to Parkinson’s disease.
2. Drugs known to increase dopamine levels (e.g., amphetamine, cocaine) produce symptoms of schizophrenia
3. The efficacy of an antipsychotic drug is correlated with the degree to which it blocks activity at dopamine receptors
Dose of drug can vary quite dramatically depending on which drug you are getting
Drugs that bind more strongly to dopamine receptors are more effective at smaller doses
4. Evidence suggests that individuals with schizophrenia have hypersensitive/ higher-than-usual dopamine release
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Evidence suggests that individuals with schizophrenia have hypersensitive/ higher-than-usual dopamine release
PET Study: they gave participants a slight amount of amphetamine (psychostimulant drug that increases dopamine function)
Exaggerated release of DA from people who have schizophrenia (exaggerated response to the amphetamine drug)
The bigger the change/the more severe the response to the amphetamine, the bigger change in a person’s positive symptoms
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Problems with the dopamine theory
| In the 80s and 90s, researchers began to realise that the theory had several major problems:
1. The newer “atypical” antipsychotic drugs produce a wide variety of changes in the brain and were just as good as traditional antipsychotics
(NOTE: they were also just as bad)
These drugs were made to reduce the side effects (motor tics)
(NOTE 2: differences might be exaggerated)
All the affective atypical medications still affected the dopamine system
2. It takes 2-3 weeks for antipsychotic drugs to work, yet their effects on dopamine receptor activity are immediate.
3. Most patients show no significant improvement to the first antipsychotic they are given even though they are all dopamine antagonist drugs
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Glutamate Hypofunction Theory
Postulates that the dysfunction of glutamate NMDA receptors particular on GABAergic interneurons leads to a decrease in GABAergic transmission
NDMAR -> mg2+ gated ionotropic glutamate receptors are dysfunctional
(Note, this theory also includes GABAergic dysfunction)
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Glutamate (and GABA) Hypofunction Theory
| Support:
Post-mortem brains show fewer glutamate receptors in schizophrenia vs. control
Glutamate antagonists like phencyclidine (PCP; angel dust) and ketamine (tranquilliser) can mimic symptoms and cognitive problems of schizophrenia
These other drugs acting on NMDAR can also have schizophrenia-like effects
NMDAR co-agonists (e.g. glycine, d-serine) which bind to another binding site on the NMDAR provide small improvement
CB1 receptor activation causes CB1-NMDAR internalisation
Chronic NMDAR antagonism (blocking NMDAR activity) changes DA transmission
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NMDAR co-agonists (e.g. glycine, d-serine) which bind to another binding site on the NMDAR provide small improvement
D-serine normally released by astrocytes which have some control over NMDAR
Administration of glycine or d-serine can have small benefits in schizophrenia
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CB1 receptor activation causes CB1-NMDAR internalisation
Very high doses of schizophrenia can exhibit psychotic-like states
Receptors that cannabis normally acts on (CB1) are often localised around NMDAR
Cannabis can pull down NMDAR from membrane which makes cell hypofunctional
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Glutamate (and GABA) Hypofunction Theory
| problems
Positive symptoms fail to respond to glutamatergic medication
Perhaps because glutamate is used across the entire brain
Changes in glutamate functioning do not lead to changes in symptomatology
(Note, this theory also includes GABAergic dysfunction)
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Autoimmune disorder
| Bone marrow transplant (BMT): “cured” schizophrenia!
Usually schizophrenia will develop across a lifespan and symptoms will manifest pretty early in life
24 yr old male with treatment resistant schizophrenia with severe delusions and hallucinations who got a bone marrow transplant for leukaemia
Showed remarkable reduction in psychotic symptoms without administration of antipsychotic drugs and drastic improvement in social functioning
2-4 years after surgical intervention showed persistent beneficial effects
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Autoimmune disorder
| Another BMT: “caused” schizophrenia!
Another patient who needed a bone marrow transplant -> only person who was a match was his brother who had schizophrenia
Shortly after transplant, the patient started to develop the positive symptoms of schizophrenia
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Autoimmune disorder
| What’s happening here with these case studies?
Hypothesis: BMT restores microglia function (immune function) may lead to improvement in function in patients schizophrenia
Autoimmune disorders more prevalent in schizophrenia patients
as autoimmune disorders often target NMDAR which may be contributing to the development of schizophrenia
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Final thoughts of schizophrenia
Lowered signal-to-noise ratio in our inherently noisy brains?
(i.e. lower threshold for what is considered a signal?)
Distribution of noisy signal as being a misattributed as a legitimate signal from a changed in signal to noise ratio
Best considered heterogeneous in nature
May be due to a variety of disorders
Best considered a neurodevelopmental disorder (but perhaps exceptions)
Involves changes in macro- and micro-circuitry across the brain
