Schizophrenia neurobiol

Question 1

AETIOLOGY - what causes it?

i) what % of the population have schz?
ii) what is the risk in a monozygotic twin?
iii) is there complete or partial penetrance?

Answer 1

i) 1% of population
ii) 50% risk in monozygotic twin
iii) partial penetrance

Question 2

GENES & ENVIRONMENT

i) what is the age of onset for females and males?
ii) what part of brain maturation goes wrong in schz?
iii) give three obsteric related factors that may predispose to schz
iv) name two things in adolescence that can increase risk

Answer 2

i) males 20-28yrs, female 26-32yrs
ii) post synaptic pruning goes wrong
iii) obstetric complications, pre natal infection, nutrition deficiencies
iv) adverse life events such as trauma, substance abuse eg cannabis

Question 3

STRUCTURAL CHANGES

i) name three structural differences seen in schz
ii) is there more or less grey matter seen?
iii) the length of which structure is associated with hallucinations in schz? what length causes this?
iv) what is the role of the above structure?

Answer 3

i) enlarged ventricles, reduced brain volume and cytoarchitectural differences in the hippocampus anc cortex
ii) a reduction in grey matter is seen
iii) the paracingulate sulcus - shorter length is seen in schz with hallucinations
iv) role in reality monitoring - shorter decreases ability to monitor reality therefore hallucinations

Question 4

what lobe is the paracingulate sulcus found in?

what is its role?

how is it implicated in schz?

Answer 4

paracingluate sulcus is found in the frontal lobe

role in reality monitoring

implicated in schz as shorter length is associated with hallucinations

Question 5

NEURODEV MODEL OF SCHZ

i) with regards to grey matter - what happens physiologically in adolescence?
ii) what happens to this in schz?
iii) when is the second peak of onset of schz in females (apart from adolesence)
iv) which lobes are most implicated in this?

Answer 5

i) physiologically grey matter is lost in adolescence
ii) in schz there is more grey matter lost than normal due to increased synaptic pruning
iii) second peak of onset is during menopause in women (45-49)
iv) increased loss of grey matter in the parietal, temporal and frontal lobes

Question 6

WINSCONSIN SORTING TASK

i) what does this task measure?
ii) how do people with schz perform?

Answer 6

i) task measures how flexibly people can think and cognitive function
ii) people with schz make lots of errors

Question 7

NEUROPHYSIOLOGY

i) which area is less active in schz patients when there is high cognitive load? what is this called?
ii) name a task where this is demonstrated
iii) what underpins the negative and cognitive symptoms in schz?
iv) name five characteristics of hypofrontality
v) which lobe may be active in schz patients and which may be quiet?

Answer 7

i) the frontal cortex is less active in high cognitive load - this is called hypofrontality
ii) demonstrated in the winsconsin sorting task
iii) absence of activity in the PFC underpins the negative and cog symptoms in schz patients
iv) hypofrontality = language poverty, social withdaw, flat affect, reduced working memory/IQ
v) active parietal lobe and quiet frontal lobe

Question 8

CHARAC OF NEURODEV MODEL OF SCHIZOPHRENIA

i) name the three characteristics of this model
ii) what are chandelier cells? what happens when they dont function properly? (rhythms)
iii) which cells do chandelier cells interact with?
iv) which type of neuron firing is seen to be abonormal?

Answer 8

i) hypofrontality, loss of grey matter and imbalanced chandelier cells
ii) chandelier cells are GABA interneurons - when they dont work properly they cause disorganised firing which give rise to abnormal oscillations and rhythms involved in working memory
iii) pyramidal cells
iv) gamma synchrony is abnormal

Question 9

SYNAPTIC PRUNING

i) in healthy controls - post 16yrs are there more excitatory or inhibitory synapses in the PFC? what does this allow?
ii) in schz patients post 16yrs are there more excitatory or inhibitory synapses in the PFC?
iii) name one other area where deficiencies are seen in schz
iv) what does this result in? (communication wise)

Answer 9

i) post 16 yrs there are more inhibitory synapses and this gives good cognitive control
ii) in schz patients there is a reduction in both inhib and excitatory synapses
iii) also see deficiencies in myelination
iv) this results in suboptimal communication between neurons and an imbalance between excitation and inhibtion

Question 10

FUNCTION NEUROPHYS CHANGES

i) when patients hear voice - is their auditory cortex activated?
ii) how is this visualised?
iii) what is a BOLD signal?

Answer 10

i) yes - the auditory cortex is activated in hallucination (when the patient hears voices)
ii) visualised on fMRI
iii) BOLD signal is seen in the auditory cortex on fMRI when auditory hallucination occurs

Question 11

WAVES AND OSCILALTIONS

i) give three roles of brain oscillations
ii) when do oscillations emerge? what do they do at this stage?
iii) what is neural synchrony?
iv) what happens when the networks are not fine tuned?
v) what is observed in oscillations in schizophrenia patients?
vi) what happens when you show a schz patient an ambigous object compared to normal controls? why does this happen?

Answer 11

i) organise brain activity, contribute to plasticity and connectivity
ii) oscillations emerge in adolescence and they connect brain areas by firing in similar phases and binding similar experiences
iii) neural synchrony is the well timed co-ordination and communication between neural populations
iv) when networks arent fine tuned there is reduced carefully timed firing and excite/inhib is out of balance
v) schz patients have reduced oscillations and synchrony
vi) when you show a schz patient an ambiguous stimulus - synchrony fails to emerge stronly and it takes longer

Question 12

when controls and patients with schizophrenia are shown an ambigious object - which response is for the patient (left or right)?

what does this show?

Answer 12

the right response is from the patient

this shows low levels of synchrony and it takes longer for it to emerge

Question 13

what are the three main neurophysiological signs seen in schizophrenia?

Answer 13

1) hypofrontality - less PFC involvement in high cognitive load
2) hyper exciteable sensory cortex - auditory cortex is activated in hallucinations
3) abnormal neural oscillations - affects cognitive function and is harder to recognise things

Question 14

PSYCHOPHARMACOLOGY

i) where do dopamine neurons have their cell bodies? where do these project?
ii) which pathway is involved in reward, reinforcement and stimlulus salience?
iii) which drugs may induce psychotic effects? what is the action of these drugs?

Answer 14

i) DA neurons have cell bodies in the midbrain that project to the forebrain
iii) mesocorticolimbic pathway
iii) DA releasing drugs such as amphetamines - agonise dopamine receptor

Question 15

ANTI-PSYCHOTICS

i) name two typical anti-psychotics
ii) which receptors do they work at and what is their action here?
iii) what do they prevent?
iv) what side effects do you get with these? how has this been overcome?

Answer 15

i) haloperidol and chlorpromazine
ii) work at D2 receptors = anatagonists
iii) prevent positive symptoms of schz such as hallucinations and delusions
iv) get parkinsonian like side effects - overcome by using atypical anti-psychotics which dont give these side effects

Question 16

name three drugs that can cause positive symptoms of schz

why do they cause this?

how can these effects be reversed?

Answer 16

cocaine, amphetamines and LDOPA

they cause this beccause they are dopamine agonists

these effects can be reverssed using D2 antagonists (anti-psychotics)

Question 17

which two things support the dopamine hypothesis for schizophrenia?

Answer 17

1) antipsychotics are dopamine antagonists and these prevent schz symptoms
2) dopamine agonists such as cocaine and amphetamines cause schz symptoms

Question 18

DOPAMINE RECEPTORS

i) which family are Gs coupled? which receptors are in this family?
ii) which family are Gi coupled? which receptors are in this family?
iii) non overlapping expression of which two receptors explains the different action of typical and atypical anti psychs?
iv) name one typical typical and one atypical and which receptor they work on?
v) which type of anti-psychotic cause extra pyramidal side effects? why do these effects manifest?
vi) what follows extrapyramidal side effects and why does this happen
vii) are side effects from typical APs temporary or permanent?

Answer 18

i) D1 receptor family are Gs coupled = D1 and D5
ii) D2 family are Gi couplied = D2,3,4
iii) non overlapping expression of D2 and D4 allow different action of antipsychotics
iv) typical = haloperidol works on D2, atypical = clonazapine works on D4 (D2 are in the striatum but D4 arent hence side effects)
v) typical antipsychotics cause extra pyram side effects - these happen because there is inhibition of DA in the striatum (caudate) due to blockage of D2 receptors
vi) EP SEs are followed by tardive dyskinesia (slow movement) due to D2 receptor supersensitivty
vii) SEs from typical APs are permanent

Question 19

give two examples of extra pyramidal side effects

what is tardive dyskinesia?

Answer 19

EP SEs = parkinsonian like symptoms such as slow movement and lack of facial expression

tardive dyskinesia is stiff and jerky face movements

Question 20

which drug has a higher affinity for the D2 receptor? haloperidol or chlorpromazine?

Answer 20

haloperidol therefore need a lower dose to get the same effect

Question 21

CLOZAPINE

i) what type of AP is this?
ii) which two receptors does it predominantly work at?
iii) what does clozapine do?
iv) what are the main side effects?

Answer 21

i) atypical
ii) works at D4 and 5HT receptors
iii) improves both positive and negative symptoms
iv) side effects are weight gain, sedation, hypersalivation, tachycardia, hypotension and neutropenia

Question 22

GLUTAMATE HYPOTHESIS

i) is schizophrenia thought to be due to lack or excess of glutamate?
ii) does agonise/antagonise NMDA receptors cause symptoms of schz?
iii) what effects does PCP cause? what receptor does it act at?
iv) what behaviours do transgenic mice with fewer NMDA receptors exhibit?

Answer 22

i) lack of glutamate
ii) antagonism of NMDA receptors = schz symptoms (reduced glutamate)
iii) PCP antagonises NMDA receptor and can cause positive, negative and cognitive schz symptoms
iv) TG mice with less NMDA receptors exhibit social isolation behaviours and withdrawal (seen in schz)

Question 23

PFC, VTA AND NAcc

i) what may cause reduced Glu transmission in the PFC?
ii) what happens when there is reduced Glu in the PFC? how does this cause schz symptoms?
iii) how does reduced Glu transmission cause hypofrontality?

Answer 23

i) NMDA antagonism
ii) less glu release from PFC will cause less activation of inhibitory GABA neurons in the VTA which means less inhibition on DA neurons in the NAcc = more DA activation in NAcc = schz symptons
iii) reduced Glu transmission causes reduced DA feedback on the PFC = hypofrontality

Question 24

where do atypical antipsychotics

i) increase
ii) decrease

DA to combat schz symptoms?

Answer 24

i) increase DA in PFC to combat hypofrontality
ii) decrease DA in NAcc to combat positive symptoms

Question 25

what are the most difficult symptoms to treat in schizophrenia?

which drugs show some improvement of these?

give four examples of these symptoms

which symptom does the winsconsin sorting test demonstrate?

Answer 25

most difficult symptoms to treat are neurocognitive deficits

atypical APs may improve these slightly

eg is neurocog symptoms are lower IQ, attention deficit, reduced working memory and planning/info processing deficits

winsconsin sorting test - demonstrates reduce working memory

Question 26

what task is this?

how do patients with schizophrenia perform? why does this happen?

Answer 26

stroop task

schz patients score lower as they find it hard to inhibit other contexual information (colour of the word) due to problems between inhibition and excitation neural networks.. there is too much noise