1
Q
1- who and where did the term come from?
2- afflicts how much of the worlds population?
3- what do ancient writings indicate?
4- what are the major symptoms of schizophrenia (cultures)
5- what cost?
6- what is schizophrenia?
A
1- Eugen Bleuler (1908) – term “schizophrenia” to refer to a break from reality
2- Afflicts 1% of the world’s population
3- Ancient writings indicate that the disorder has been around for thousands of years
4- The major symptoms of schizophrenia are universal, similar across cultures
5- Monetary cost - exceeds the cost of all cancers and is associated with much higher (13x) suicide rate compared to the general population
6- Schizophrenia is a syndrome – ‘a collection of signs and symptoms of unknown aetiology’ (Insel, 2010, Nature)
2
Q
Symptoms of Schizophrenia:
- categories?
- symptom onset?
- when do they appear?
- what symptoms are the first to emerge?
A
- Three categories of symptoms: positive, negative, and cognitive
- Symptom onset is usually in early adulthood but can happen earlier or later
- Appear gradually, over a period of 3-5 years.
- Negative symptoms are the first to emerge, followed by cognitive symptoms. The positive symptoms emerge last.
3
Q
Positive Symptoms:
- how do they make themselves known?
- what do they include?
- explain one in depth
A
- Make themselves known by their presence (excess).
- They include thought disorders, delusions and hallucinations
- Thought disorders:
– disorganized, irrational thinking - probably the most important symptom of schizophrenia
– great difficulty arranging thoughts logically, and sorting out plausible conclusions from absurd ones.
– during conversation they jump from one topic to another as new associations come up.
– sometimes utter meaningless words or choose words for rhyme rather than for meaning.
4
Q
What are delusions and what are the types?
A
Delusions are beliefs that are contrary to fact. There are many types:
- persecution - false beliefs that others are plotting and conspiring against oneself.
- grandeur - false beliefs about one’s power and importance (godlike powers, special knowledge that no one else possesses)
- control related to persecution i.e the person believes that he or she is being controlled by others through radar or a tiny radio receiver implanted in his or her brain.
5
Q
What are hallucinations and what are the types?
A
Hallucinations are perceptions of stimuli that are not actually present.
- Most common are auditory, but they can involve any of the other senses.
- Typically, voices talk to the person, order them to do something, scold the person for his or her unworthiness or utter meaningless phrases.
- Olfactory hallucinations are also fairly common and they often contribute to the delusion that others are trying to kill them (smelling things which are not there)
6
Q
Negative Symptoms
A
Known by the absence or diminution of normal behaviours:
- flattened emotional response
- poverty of speech
- lack of initiative
- persistence
- anhedonia
- social withdrawal
7
Q
What do cognitive symptoms include?
A
- difficulty in sustaining attention
- low psychomotor speed (the ability to rapidly and fluently perform movements of the fingers, hands, and legs)
- deficits in learning and memory
- poor abstract thinking
- poor problem solving
8
Q
Cognitive Symptoms:
- what are neurocognitive deficits associated with?
- what did Weinberger (1988) suggest?
A
- All neurocognitive deficits are associated with frontal lobe hypofunction
- Weinberger (1988) suggested that the negative symptoms of schizophrenia are caused primarily by hypofrontality, decreased activity of the frontal lobes, the dlPFC in particular
– Lower performance in IQ tests
– Planning and information processing deficits
– Attentional deficits (e.g. Stroop test)
– Working memory deficits (e.g. Wisconsin Card Sorting Test)
– Sensory-motor gating deficits (P50 and PPI tasks)
– Anti-saccade task
– Oculomotor function (eye tracking)
9
Q
dlPFC in controls vs schizophrenia
A
less activation in frontal lobes and dlPFC compared to controls
10
Q
The Stroop task
A
- The instructions are to name the colour of the ink in two conditions: congruent (word and ink colour are in agreement) and incongruent (colour of ink and word are not in agreement)
- Schizophrenia patients are slower and less accurate
- Involves inhibiting the tendency to read the words
11
Q
Wisconsin Card Sort Test
A
Stack cards in different piles- change strategies until you do what they expect you to do. People with sz are unable to change their strategy and organise their cards in a different way.
Normally, during the task, there is an increase in regional blood flow to the dlPFC as measured by fMRI
12
Q
What are sensory-motor gating deficits?
A
Difficulties screening out irrelevant stimuli and focusing on salient ones
13
Q
Sensory-Motor Gating Deficits
1
A
P50 signal in ERPs (Event-Related Potentials)
- Presented with 2 auditory stimuli (2 clicks) 500ms apart
- Healthy response - P50 wave to 2nd click is 80% diminished whereas in schizophrenic patients there is no change. Sz pp’s respond in the same way to the second click.
14
Q
Sensory-Motor Gating Deficits
2
A
- Pre-Pulse Inhibition (PPI)
- When a weak stimulus precedes a startle stimulus by ~100ms the normal response is to inhibit the startle
- People with schizophrenia do not inhibit the startle
15
Q
Oculomotor Function
A
Smooth pursuit - Tracking a moving stimulus
The eye movements of schizophrenic patients are not smooth compared to controls (“catchup” saccades)
16
Q
Structural Differences:
What did Weinberger and Wyatt (1982) do and find?
A
- Weinberger and Wyatt (1982): CT scans of 80 schizophrenics and 66 healthy controls of the same mean age (29y) and measured the area of the lateral ventricles (blind study)
- The relative ventricle size of the schizophrenic patients was more than twice as big as that of normal control subjects
- Reduced brain volume (less grey matter) in temporal, frontal lobes and hippocampus
- Faulty cellular arrangement in the cortex and hippocampus
17
Q
Heritability and Genetics:
- what do both adoption and twin studies show?
- so far…
- what does having a “schizophrenia gene” cause?
A
- Both adoption studies and twin studies indicate that schizophrenia is a heritable trait although it is not due to a single dominant or recessive gene
- So far, no single gene has been shown to cause schizophrenia. Rather, several genes are involved.
- Having a “schizophrenia gene” causes a susceptibility to develop schizophrenia which may be triggered by environmental factors.
18
Q
Genetics of Schizophrenia
- what does one rare mutation involve?
- explain about this gene?
A
- One rare mutation involves a gene known as DISC1 (disrupted in schizophrenia 1)
– involved in the regulation of neurogenesis, neuronal migration, postsynaptic density in excitatory neurons, and mitochondria function
– Its presence appears to increase the chance of schizophrenia by a factor of 50
– Also increases the incidence of other mental health conditions, including Bipolar Disorder, and Autism Spectrum Disorder (Kim et al., 2009).
19
Q
Paternal Age
- what does the effect of paternal age provide?
- who are more likely to develop schizophrenia
- most likely due to?
– what happens following puberty?
– in contrast…
A
- The effect of paternal age provides further evidence that genetic mutations may affect the incidence of schizophrenia (Brown et al., 2002; Sipos et al., 2004).
- The children of older fathers are more likely to develop schizophrenia.
- Most likely due to mutations in the spermatocytes, the cells that produce sperm.
- Following puberty, these cells divide every 16 days, which means that they have divided approximately 540 times by age 35
- In contrast, a woman’s oocytes divide 23 times before birth and only once after that.
20
Q
Percent developing schizophrenia
A
Higer incidence in DZ (17%)
MZ is even higher (48%)
One one hand we have genetic contribution but on the other hand genetics cannot explain everything because we have a big percentage here that is attributed to unknown environmental factors.
21
Q
Twin Studies
- MZ twins?
- when does the formation of MZ twins occur?
- what happens if this occurs before day 4?
- what happens if this occurs after day 4?
- what was the concordance rate for monochrionic MZ twins?
A
- MZ twins are genetically identical, but they also share the same intrauterine environment. However, the prenatal environment of monozygotic twins is not always identical
- The formation of MZ twins occurs when the blastocyst splits in two.
- If this occurs before day 4, the two organisms develop independently, each forming their own placenta – dichorionic
- If this occurs after day 4, the two organisms become monochorionic - share a single placenta.
- The concordance rate for monochorionic MZ twins was found to be 60% vs 32% in dichorionic MZ twins (Davis and Phelps, 1995)
22
Q
The ‘early’ neurodevelopmental model:
A
- Events in early life (prenatally) cause deviations from normal neurodevelopment and these lie dormant until the brain matures sufficiently to call into operation the affected systems (Murray & Lewis, 1987)
- Early events such as infections, obstetric complications, nutritional deficiencies etc. provide evidence in support of this theory.
23
Q
Early evidence suggesting deviations in brain development
A
- Home movies from families with a schizophrenic child (Walker et al 1994,1996)
– Independent observers examined the behavior of the children
– Those who subsequently became schizophrenic displayed more negative affect in their facial expressions and were more likely to do abnormal movements. - In 1972, 265 Danish children aged 11–13 years, were videotaped briefly while eating lunch (Schiffman et al. 2004)
– Blind raters, found that the children who later developed schizophrenia displayed less sociability and displayed deficient psychomotor functioning.
24
Q
Neurodevelopmental Theories
Name 2
A
The ‘late’ neurodevelopmental model:
- schizophrenia may result from an abnormality or deviation in adolescence, when synaptic pruning takes place (Feinberg, 1982/3).
“Two-hit” model (Fatemi & Folsom, 2009; Keshavan and Hogarty, 1999):
- Atypical development in schizophrenia takes place during 2 critical time points: early brain development and adolescence.
- Early developmental insults may lead to dysfunction of specific neural networks that would account for premorbid signs
- During adolescence, excessive synaptic pruning and loss of plasticity may account for the emergence of symptoms.
25
When is increased synaptic pruning evident?
In adolescence who later on develop schizophrenia
26
Timeline of Schizophrenia Development
Birth- obstetric complications, prenatal infection, nutritional deficiency → Adolescence- adverse life events, substance abuse (cannabis use- 6x risk) → schizophrenia
Genetic- susceptibility genes between birth and adolescence
27
The Dopamine (DA) Hypothesis:
- what does it suppose schizophrenia is caused by?
- how do positive symptoms of schizophrenia arise?
- how do negative and cognitive symptoms of schizophrenia arise?
- Proposes the schizophrenia is caused by abnormalities in DA functioning in the brain
- Overactivity of DA in the mesolimbic system results in the positive symptoms of schizophrenia
- Underactivity of DA in the mesocortical system results in the negative and cognitive symptoms of schizophrenia
28
DA Hypothesis: Positive Symptoms
In healthy brain we have normal levels of dopamine secreted in the VTA and Nac where as in the patients brain we have a lot of dopamine being released and this is giving rise to a lot of the positive symptoms.
29
DA Hypothesis
Negative, Cognitive Symptoms
In healthy brain we have normal release in the dlPFC so people are performing well in neuropsychological tasks where as in a patients brain there is hypofrontality and less dopamine in dlPFC giving rise to negative, affective and cognitive symptoms.
30
dopamine/ symptoms applied to:
- mesolimbic pathway
- mesocortical pathway to DLPFC
- mesocortical pathway to VMPFC
- nigrostriatal and tuberoinfundibular pathway
- Mesolimbic pathway: lot of dopamine, positive symptoms.
- Mesocortical pathway to DLPFC: low release of dopamine, cognitive, negative symptoms
- Mesocortical pathway to VMPFC: low release of dopamine, negative symptoms
- nigrostriatal and tuberofundibular pathways: normal dopamine
31
What do DA agonists induce and explain
Psychosis
- DA agonists produce symptoms that resemble the positive symptoms of schizophrenia.
- These drugs include **amphetamine**, **cocaine**, **methylphenidate** and **L-DOPA**.
- The symptoms that they produce can be alleviated with antipsychotic drugs
- strengthens the argument that the antipsychotic drugs exert their therapeutic effects by blocking DA receptors.
32
DA antagonists:
- what did Henri Laborit (mid 20thce) find?
- what related compound was developed in 1952?
- explain about this compound
- Henri Laborit (mid 20thce): French surgeon who discovered that a drug used to prevent surgical shock also reduced anxiety.
- A related compound called **chlorpromazine (CPZ)** was developed in 1952 which had dramatic effects on schizophrenia.
- CPZ is a **DA antagonist** – first antipsychotic
33
Antipsychotic drugs:
- since the discovery of CPZ, what has been found?
- what are the 2 families of DA receptors?
- what property do these drugs have in common?
- Since the discovery of CPZ, many drugs have been developed for the treatment of schizophrenia – **typical antipsychotics**
- Two major families of DA receptors:
1) D1-type family (Gs coupled): D1 & D5
2) D2-type family (Gi coupled): D2, D3, D4
- These drugs have one property in common: They **block D2 receptors**
34
Effective dose and D2 receptor binding affinity
If we have a drug that binds well to the D2 receptor we can give a small dose and be able to treat the symptoms of schizophrenia where as if we have a low affinity drug it means that it doesn’t bind very well and we may need to increase the dose. A lot of antipsychotics seem to bind to the D2 receptor in order to have an effect and ameliorate the positive symptoms of sz.
35
More evidence in support of DA’s involvement:
- SPECT study as...
- IBZM...
- measured...
- what does more displacement of IBZM mean?
- what correlated with positive symptoms?
- SPECT study using Iodobenzamine (IBZM), as a radiotracer.
- IBZM is a D2 receptor reversible ligand which means that it will compete with DA for binding to that receptor
- Measured displacement after treatment with amphetamine in striatum (Abi-Dargham 1998, Am J. Psychiatry, 155, 761-70)
- More displacement of IBZM means more DA activity
- More DA activity in striatum correlated with positive symptoms
36
More evidence in support of DA’s involvement
They saw that in patients with sz there was greater displacement of IBZM in the brain when the patients were given amphetamine suggesting they were releasing a lot more dopamine than the control.
Those that were displacing a lot of the IBZM were having a lot of the positive symptoms suggesting there is a connection with dopamine in patients compared to controls.
37
Treatment with Typical Antipsychotics
- These drugs eliminate, or at least diminish the positive symptoms in most of the patients. About 20-30% do not respond to these drugs (meaning they cannot be helped if they are given this drug)
- Long-term treatment leads to at least some symptoms resembling those in **Parkinson’s disease**: slowness in movement, lack of facial expression, and general weakness.
- A more serious side effect develops in ~1/3 of all patients who took the drugs for an extended period: **tardive dyskinesia** patients with tardive dyskinesia are unable to stop moving.
38
Newer Drugs Atypical Antipsychotics:
- where do atypical antipsychotics work?
- what do atypicals not have?
- improve? (x2)
- Atypical antipsychotics work in treatment-resistant patients
- Atypicals do not have the Parkinsonian side-effects due to the fact that they have lower affinity for the D2 receptors
- Improve both positive and negative symptoms of schizophrenia
- Also improve the performance in neuropsychological tests which is not the case with typical antipsychotics
39
Clozapine
- what was it?
- affinity?
- usage?
- only antipsychotics to...
- still considered to be...
- **Clozapine,** the first of the atypical antipsychotic drugs (followed by others: *risperidone, olanzapine, ziprasidone, and aripiprazole)*
- Has lower affinity for D2 and higher affinity for other DA receptors (D3, D4 and even 5HT)
- Although it is highly effective it is still not widely used – despite international consensus to use it when other drugs have failed
- The only antipsychotic to reduce suicide rates in schizophrenics
- Still considered to be tricky due to its side effects: weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia etc.
40
Problems with the Dopamine hypothesis
- It explains only a part of schizophrenia (positive symptoms not negative symptoms)
- Atypical antipsychotic drugs e.g. Clozapine (with weaker anti-dopaminergic activity) are better antipsychotics.
- Negative symptoms are caused by under-activity in the mesocortical dopamine pathway
- So, dopamine underactivity is the problem rather than dopamine overactivity
41
The Glutamate System
- Glutamate is the major excitatory neurotransmitter in the central nervous system and the most prevalent one (the king of neurotransmission)
- Many neurons in the brain, including all neurons that project from the cerebral cortex, use glutamate as their neurotransmitter.
- In mammalian brains, glutamate is balanced with GABA (main inhibitory chemical transmitter)
- Both neurotransmitters influence almost every other chemical and brain area.
- Evidence implicates **NMDA receptors** in schizophrenia
42
NMDA Receptor
- NMDA receptor is an ionotropic receptor (tetramer NR1 & NR2)
- At rest the channel is blocked by Mg2+
- When open it allows for Ca2+ influx
- Activation of NMDA can support learning and memory (LTP, spine proliferation and trophic effects) but too much can be excitotoxic.
43
NMDA and Schizophrenia
NMDA receptors comprise a critical component of developmental processes which include:
- Development of neural pathways
- Neural migration
- Neural survival
- Neural plasticity
- Neural pruning of cortical connections
- Apoptosis
44
Glutamate Hypo-functioning Hypothesis (Olney and Farber, 1995)
Schizophrenia is due to NMDA receptor hypofunction which may explain...
a) Why there are so many treatment-resistant negative symptoms
b) Why the onset is in early adulthood
c) Why the disorder is associated with structural changes and cognitive deficits.
45
Glutamate Hypofunctioning Hypothesis:
- what can cause positive, negative, and cognitive symptoms of schizophrenia?
- what are both of them?
- what seem to improve both positive and negative symptoms of schizophrenia
- evidence in support from...
- The drugs Phencyclidine (**PCP**, also known as “angel dust”) and **ketamine** (“Special K”), can cause positive, negative, and cognitive symptoms of schizophrenia
- Both of them are NMDA receptor antagonists
- Glutamate agonists seem to improve both positive and negative symptoms of schizophrenia
- Evidence in support from animal genetic studies with NMDA receptor subunits as well as GWAS
46
Positive and Negative Symptoms: Role of the PFC
- The negative and cognitive symptoms produced by ketamine and PCP are caused by...
- what did Jentsch et al. (1997) do?
- The negative and cognitive symptoms produced by ketamine and PCP (which are blocking NMDA receptors) are caused by a decrease in the metabolic activity of the frontal lobes.
- Jentsch et al. (1997) administered PCP to monkeys twice a day for two weeks.
-- A week later, tested the animals on a task that involved reaching around a barrier for a piece of food
-- Performance depends on the function of the PFC (animals with lesions of the PFC perform poorly).
-- Control monkeys performed well, but those treated with PCP showed a severe deficit.
47
Glutamate hypothesis: Positive Symptoms
In the healthy brain we have glutamatergic neurons which are synapsing on GABA-ergic interneurons. The GABA-ergic neurons are synapsing on another set of glutamatergic neurons and these project unto the Mesolimbic system into the VTA to control the release of dopamine in the mesolimbic system. Here everything is balanced and well.
In the patients brain, remember The glutamatergic hypothesis implicates a hyper functioning NMDA receptor that is located on a GABA-ergic interneural in the prefrontal cortex. In this situation if we have a glutamatergic interneuron that is stimulating this GABA-ergic interneuron this interneuron is not going to function properly and inhibit/ silene this glutamatergic neuron. This inhibited symbol is projected from the cortex to the mesolimbic system.
48
Glutamate hypothesis: Negative & Cognitive Symptoms
healthy brain- glutamatergic neuron synapsing on the GABA interneurton synapsing/ inhibiting/ controlling the release of glutamate that will be projecting down to the mesolimbic area. There is another inhibitroty IN. This gabaergic interneuron is functioning properly. The GABA is stimulated so its going to inhibit this postsynaptic neuron so its going to regulate how much dopamine is going to be released in the dlPFC and the vmPFCand everything is working fine.
patient- problematic IN, it doesnt have a functioning NMDA receptor. The glutamate is going to synapse and stimulate this gabaergic IN but this is not functioning so we have a disinhibited powerful glutamate signal that comes down the VTA. Its going to powerfully stimulate the GABAergic IN and massively inhibit this dopamine projection. This is how we have low levels of dopamine in the PFC and explain the negative amd positive symptoms of schizophrenia.
49
Hypo-functioning NMDA Receptors Theory
- This theory is more comprehensive - it can explain the positive, negative & cognitive symptoms of schizophrenia
- It accounts for the lack of effectiveness of DA antagonists in treating schizophrenia
- Hypo-functioning NMDA receptors can account for both the excessive DA release in the mesolimbic DA system as well as the reduced release of DA in the prefrontal cortex
50
Microglial activation and schizophrenia
- The brain’s immune cells are hyperactive in people who are at risk of developing schizophrenia
- Many animals studies show a link between pro-inflammatory agents and schizophrenia symptoms
- The symptoms are reversed upon treatment with antipsychotics or treatment with antibiotics that reduce microglial activation
- Support the evidence for prenatal or perinatal infection and the increased risk for schizophrenia
51
What is found in:
PET imaging in healthy volunteers, high-risk subjects and patients with schizophrenia
Stepwise elevation in microglial activity as the severity of the illness increases
52
Recent Genome-Wide Association Studies of schizophrenia
- Identified 100+ genetic loci that contribute to schizophrenia risk.
- The dopamine-receptor gene, DRD2, GLU receptor subunits etc are associated with risk of schizophrenia.
- Most significant association is on chromosome 6 which includes a region of genes involved in acquired immunity (major histocompatibility complex - MHC- a bunch of genes that are activated by the immune system).
53
Microglia
- In healthy conditions they are in a ramified state and survey the brain for pathogens or debris
- Upon identification of a threat they become activated (amoeboid morphology)
- Their function goes beyond the immune system – involved in a range of homeostatic functions in a healthy brain such as:
-- Neuronal cell death and survival
-- Synaptogenesis
-- Synaptic pruning etc
54
Microglia in the CNS: 3 things
Ramified, Activating, Amoeboid
When receiving a signal, starts to activate and swell up. Amoeboid stage is the most swelled.
55
Microglial activation and schizophrenia in animal studies
- Interestingly, microglial activation is not instantaneous in response to infectious agents
-- grows steadily throughout the lifespan, reaching a peak in late adolescence and early adulthood
- Thus, a pre- or perinatal infection *primes* microglia and this priming may interact with cells in the developing nervous system
- May lead to a subtle rearrangement of synaptic circuitry resulting in behavioral impairment in adolescence
56
Oestrogen (estrogen) Hypothesis of Schizophrenia
- what is estrogen?
- ____ is secreted mainly by ____
- what is there in women?
- what does estrogen seem to play a role in?
- Estrogen is the primary “female” sex hormone with 17β-estradiol being the most potent form
- 17β-estradiol is secreted mainly by the ovaries, fat, breasts and the brain (neuroprotective effect)
- In women there is a 2nd peak onset of schizophrenia at age 45-50y (menopause)
- Estrogen seems to play a protective role against the development of schizophrenia (buffer)
57
Estrogen Hypothesis of Schizophrenia
Women seem to have...
- Less severe course, less severe negative symptoms
- Later onset which is linked to better prognosis
- Better response to antipsychotic treatment, fewer hospitalizations and less disability (self-care, remain employed, more likely to be married, keep family and friends)
- Support the hypothesis that sex hormones may also play a role in the aetiology and treatment of schizophrenia
B+B
flashcards
Decks in class (12)
# Cards
-
Introduction to brain and behaviour20
-
Neurodevelopment 141
-
Neurodevelopment 222
-
Neurogenetics56
-
Neurotransmission and Neuromodulation48
-
Neurotransmission 2: dopamine, serotonin, acetylcholine19
-
Stress, anxiety and aggression51
-
Affiliative and Reproductive behaviour53
-
Learning and Memory47
-
Pain51
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Sleep and Circadian Rhythms53
-
Schizophrenia57
