4a) Schizophrenia: Neurobiological hypothesis Flashcards
What are schizophrenia symptoms?
- Positive symptoms
- delusions
- hallucinations –> most common: auditory
- delusion of control –> outside sources command you - Negative symptoms
- blunted affect
- alogia (= inability to speak..)
- avolition (=lack of motivation/drive)
- asociality
- anhedonia - Cognitive symptoms
- memory
- attention
- executive functions
What are the stages of disease?
- Premorbid phase
- Prodromal phase: Prevention
- Early at-risk of psychosis state: basis symptoms (BS), functional state-biological trait criterion
- late at-risk of psychosis stae: attenuated positive symptoms (APS), brief limites intermittent psychotic episode (BLIP) - Early psychosis: Treatment
- transition criterion
–> some signs before first psychosis
- changes over time –> early symptoms important
Psychosis: prevalence/distribution
- difficult to relate to
- lifetime prevalence 6% in general population
–> schizophrenia: prevalence 1% - 8% have psychotic experiences
> 4% have psychotic symptoms
–> 3% have psychotic disorder
Recovery of schizophrenia
- very heterogenous outcome after diagnosis
–> diagnosis does not mean that normal life is impossible
–> don’t understand the neurobiological processes of variety
recovery = improvement in clinical and social domains for at least 2 years (can perform in social roles, almost no symptoms)
- despite major changes in treatment –> no increase in proportion of recovered cases
–> higher recovery in poorer countries: why?
Symptomatic trajectories in first episode psychosis
- measurement by interview
- four trajectory classes:
1. remitting-improving (58.5%)
2. late decline (5.6%)
3. late improvement (5.4%)
4. persistent (30.6%)
–> symptomatic course is heterogeneous and intrinsically difficult to predict
What are risk factors of schizophrenia?
- first and second wave hits occur in utero to adolescence –> first episode during early adulthood
- Ethnic minority status and urbanicity
- increased socio-environmental adversities
- over all catergories rather significant - Genetics
- Complications during pregnancy and birth
- Exposure to chemicals
- neurodevelopmental –> no complete understanding why
- Brain formation
- in utero to childhood
- neurogenesis, neuronal proliferation, migration and differentiation
- synaptogenesis
- gliogenesis
- sub-cortical myelination - Brain reorganisation
- childhood to adolescence
- cortical myelination
- dendritic arborisation
- circuit plasticity
- synaptic pruning
- sexual maturation - Brain upkeep
- adulthood
- cerebral housekeeping
- glial support
- neuroprotection and/or neurorestoration
- myelin repair
Pathopsychological models of schizophrenia
- altered plasticity and maybe dysconnectivity/misconnection in PFC
- cognitive deficits and negative symptoms
E/I imbalance PFC
- excitatory and inhibitory (glutamate and GABA)
–> feedback circle from glutamate pyramidal cells to interneurons leads to reduced inhibition and more dopamine release in midbrain
- cognitive and negtiave symptoms
- dopamine dysfunction
- abberant saliency and positive symptoms
Dopamine imbalance
- no control, more dopamine release
- normally E/I balance to control/inhibit neuromodulatory systems in midbrain/brain stem
–> brain might try to adapt and therefore ‘develops’ symptoms/illness over time
- start with deficit –> leads to reactions and changes till disease
- pyschotic symptoms
I/E imbalance: How do schizophrenia patients perform in working memory tasks?
Worse performance
- in schizophrenia patients with medium to large effect sizes
- in high-risk subjects who later develop psychosis
–> involvement of fronto-parietal networks, dysfunction of dlPFC in schizophrenia
working memory = maintenance and performance of information that is no longer directly available to the senses (n-back tasks)
E/I imabalance: MRS glutamate, working memory and schizophrenia
- three groups: control, medicated, unmedicated
- significant correlations between behavioural performance and glutamate measure in voxel
- unmedicated performed worst, largest effect of glutamate (?)
Dopamine: Why? - dopamine hypothesis
- effectiveness of antidopaminergic medication
- psychotomimetic effect of dopaminergic drugs
- neurochemical neuroimaging
- Parkinson’s patients treated for dopamine sometimes show similar symptoms as schizophrenia patients
- all anti-psychotic are D2-antagonists
–> D2 occupancy is a contributing factor for the mechanism of antipsychotic effects for some but not all antipsychotic medications - other dopermingeric drugs can induce psychosis (cocaine, methaamphetamines)
Dopamine system and doperminergic imaging targets
- somata in midbrain (SNc and VTA) contain 50-100,000 dopamine neurons
Different imaging targets
- VMAT2 availability
- DAT availability
- DA receptor availability
- DA synthesis
- DA release capacity
- D2 receptor occupancy by DA
- elevated striatal dopamine function in patients
- higher synthesis capacity
- higher dopamine release
Dopamine release capacity in patients
- radioactive marked ligant to measure activity and availability of receptors
–> measure receptors - give methamphetamine - measure again
–> drug quickly releases dopamine - patients release more dopamine than controls –> BUT heterogeneous
- correlated in interviews with increase in psychotic (positive) symptoms
- pharmacological stubstances can act on positive symptoms but do little for negative symptoms
Dopamine synthesis capacity in patients
- higher capacity in patients (and ARMS risk group) than controls
- correlated in interviews with increase in psychotic (positive) symptoms
- pharmacological stubstances can act on positive symptoms but do little for negative symptoms
Dopamine and psychosis
aberrant salience = links dopamine dyfunction to psychosis
- stress-induced or chaotic activation of dopamine release may attribute incentive salience to otherwise irrelevant stimuli
- must be involved in the pathogenesis of delusional mood and other positive symptoms
- biased cognitive schema
–> minority/immigration risk
–> exclusion may lead to certain cognitive schema and then contribute to paranoid interpretation
Function of dopamine
reward, motivation, learning
- unexpected/not predicted event leads to dopamine signalling
–> dip in signalling when predicted reward is not received
- reward prediction error = comparison of expectation and outcome
–> can be used at next tiral to make sense of the environment (learn)
Reinforcement learning
- can be modelled mathematically, use Q values to choose action (most rewarding) –> compare expectation to outcome
Reward prediction errors in psychosis
alterations in patients
(combine prediction error signalling fMRI and PET dopamine synthesis capacities)
- poorer performance than controls, more inverse decision noise
- prediction errors associated with negative symptoms
- no differences in striatal dopamine between healthy controls and patients
- differences between subgroups and symptom association
- the higher dopamine capacity, the higher the negative effects
- in healthy subjects positive correlation between dopamine synthesis (PET) and prediction error (fMRI) –> in patients none/slight
