Schizophrenia

Question 1

who was Emil Kraepelin (1898)

Answer 1

• at this time SZ patients were first systematically described as separate psychiatric category of patients
• first to describe symptoms of SZ patients
• Described symptoms of patients as ‘dementia praecox’:
• dementia = global disruption of perceptual and cognitive processes
• praecox = early adulthood onset
• Main symptoms: impairments in attention, memory and goal-directed behaviour
• Described condition as progressive, no return to premorbid functioning

Question 2

who was Eugen Bleuler (1911)

Answer 2

• Reformulated dementia praecox
• Coined the term schizophrenia:
• schizo = split
• phrene = mind
• Characterised fragmented thinking
• First to distinguish between positive and negative symptoms

Question 3

what is Schizophrenia?

Answer 3

• as defined in the Diagnostic and Statistical Manual of Mental Disorders (or DSM), schizophrenia is characterized by a combination of positive and negative symptoms and these can be demonstrated to variable degrees
• one patient could show predominantly positive symptoms, but not as many negative symptoms, while another patient may show mainly negative symptoms.
• has positive and negative symptoms as well as cognitive deficits (70-80% of patients have cognitive deficits)

Question 4

what are positive (type 1) symptoms?

Answer 4

delusions:
- false belief despite evidence to contrary, distorting reality (e.g. patient beliefs someone is plotting against them)
- thought insertion
- thought withdrawal
- thought broadcasting
- not being in control of own actions

Hallucinations:
- perceptual experience seems real in absence of physical proof; most common: auditory, visual, olfactory (e.g seeing an animal or person that isn’t real)

Disorganised behaviour
- can affect speech, difficulties with routine tasks, inappropriate behaviour

Question 5

what are negative (type II) symptoms

Answer 5

diminished emotional expression
- affect: blunted affect, mood or emotional state, limited range of emotions
- alogia: poverty of speech, lack of conversation

Avolition
- apathy (lack of motivation)
- social withdrawal
- Anhedonia: inability to feel pleasure

Question 6

what are cognitive deficits?

Answer 6

• substantial impairment in overall cognitive performance (occurs in most SZ patients)
• can be variable across patients
  most common deficits in:
• executive functions/cognitive control (incl. verbal frequency and problem solving
• attention (incl. vigilance)
• processing speed
• memory (working memory, episodic memory)
• social cognition

Presence of cognitive deficits associated with poor daily functioning and quality of life

Question 7

tetsing for cognitive deficits

Answer 7

• Impairments in cognitive functions already detectable in childhood/adolescence  neurodevelopmental disorder
• Objective assessment of cognitive impairments and subjectively perceived impairments only weakly correlated
• anosognosia for cognitive deficits (in particular, in individuals with more severe deficits)

Question 8

Schizophrenia as a neurodevelopmental disorder

Answer 8

• SZ is a neurodevelopmental disorder
• typically develops during late adolescence
• cognitive impairments can often be detected much earlier, i.e. in childhood or early adolescence
• Brain abnormalities slowly emerge during adolescence, therefore it is described as neuro developmental condition.
• Combination of genetics and environment (~80% heritable)
• Prevalence of SZ: 1%

Question 9

what are the genetic risk factors of developing SZ?

Answer 9

• Children or siblings of affected individuals 10 x more likely to develop SZ
• Polygenic disorder: at least 108 genes implicated
• Genetics only explain small percentage of cognitive variance

Question 10

what are the environmental risk factors of developing SZ?

Answer 10

• adverse events prenatally or perinatally (adverse events before or during birth) (e.g. poor maternal nutrition, infection, obstetric complications)
• Perinatal hippocampal injuries in rats ➟ development of abnormal dopamine organization in prefrontal cortex
• Contact with certain viruses in early childhood might increase risk
• Growing up in urban environment
• Air pollution
• Drugs: some individuals develop SZ after taking certain drugs, e.g. cannabis

Question 11

what are the 4 neurotransmitters involved in SZ?

Answer 11

• Dopamine = linked with positive symptoms and attention, WM, cognitive control
• Acetylcholine = linked to attention and memory
• Glutamate (Glu) = main excitatory neurotransmitter
• GABA = main inhibitory neurotransmitter

Question 12

what is the dopamine hypothesis?

Answer 12

dopamine hypothesis:
- Important role of mesocortical dopaminergic pathway (from tegmentum)
- dopaminergic agonist, i.e. drugs that increase dopamine levels, like cocaine, amphetamine or L-Dopa, can induce psychotic symptoms, which resemble positive symptoms in individuals with schizophrenia
- plausible to assume a crucial role of the DA system in schizophrenia, with high levels of dopamine causing positive symptoms
- Disturbances in this transmitter system could explain various cognitive impairments seen in individuals with schizophrenia

• Typical antipsychotic medication reduces DA levels in the brain
• these reduce positive symptoms
• but not very effective at attenuating the negative symptoms; on the contrary, they sometimes even worsen the negative symptom

Question 13

dopamine hypothesis: dissociation between cortical and striatal DA

Answer 13

• suggested that there is a dissociation between cortical and striatal DA.
• There might be too little DA in cortical areas, i.e. a hypo-dopaminergic state
• there might be too much DA in the striatum, i.e. a hyper-dopaminergic state in the striatum
• DA levels fluctuate in individuals with SZ over time, cognitive symptoms much more stable -> close link is unlikely

Overall, the DA hypothesis cannot be the whole story. Usually, modulations in one transmitter system can also affect other neurotransmitter systems

Question 13

Glutamate (Glu)

Answer 13

• glutamate plays a central role in schizophrenia, and that the dysregulation of the dopaminergic system is only secondary to impaired glutamatergic functions
• Glu is the main excitatory neurotransmitter in the brain, and Glu levels can modulate DA release in the Ventral Tegmental Area, so DA and Glu systems are not working independently, but they interact.
• Postmortem brains of schizophrenia patients: loss of Glu neurons in ACC (and other brain areas; Squires et al., 1993)

Question 14

Moghaddam & Javitt (2012): 2 phases of Glu modulations in SZ patients

Answer 14

1. NMDA-mediated interneuron dysfunction ➜ loss of inhibitory control, increased Glu levels
2. Glu-induced excitotoxicity ➜ loss of Glu connections; decreased Glu levels

Question 15

what is Magnetic Resonance Spectroscopy (MRS)

Answer 15

• MRS has been used to measure neurometabolites in vivo. The advantage of MRS, compared to PET studies, for instance, is that neurotransmitter levels can be quantified without using radioactive tracers as MRS can be done by using a standard MRI scanner.
• The methods for MRS are still evolving and scanning sequences are being optimised for certain neurotransmitters so the results of these MRS studies have been quite mixed in the past, but they will get more precise over time.

Question 16

Meta analysis of MRS studies in psychosis patients, Sydnor & Roalf (2020)

Answer 16

• meta-analysis to find a common pattern in neurometabolite changes in psychosis patients compared to healthy controls
• found no significant different between patients and healthy controls in that study
• results are mixed with some studies finding decreases in Glu and others finding increases. However, in a meta-analysis you can combine all the available data.
• overall, patients show reduced glutamate levels, which would be expected in chronic schizophrenia patients
• A similar finding has been reported for glutathione, a major antioxidant in the brain, that has a close relationship to glutamate and is also reduced in individuals with schizophrenia.

Question 17

Neurotransmitters and the multiple systems affected

Answer 17

• Newer, atypical antipsychotics target a variety of neurotransmitters, e.g. DA in addition to serotonin and adrenaline
• Neurotransmitter systems seem to be affected to different degrees in patients; might explain the variability between patients and ehy available drugs are not effective to same extent in all patients

Question 17

Differences in brain anatomy in patients with SZ and without

Answer 17

Post-mortem studies have shown that brains of schizophrenia patients weigh less than the average weight of neurologically healthy people. This weight loss might be explained by the following observations:

• SZ patients show enlarged ventricles, which suggests a loss of / or fewer long range white matter fiber connections. Examples for enlarged ventricles can be seen on the pictures on the right side
• Individuals with schizophrenia have a reduced number of neurons in prefrontal cortex areas and thinner parahippocampal gyri, indicating fewer cells in these structures as well.
• Neurons in prefrontal and hippocampal areas show a different structure in patients compared to controls

Question 18

Meta-analysis investigated grey matter (GM) loss in individuals with SZ Liloia et al. (2021, NBR)

Answer 18

• In chronic SZ GM is reduced in
• the medial frontal and anterior cingulate cortex
• the insular cortex is affected bilaterally
• Left thalamus and caudate
• Amygdala bilaterally
• These structures play a role in decision-making, for example. The amygdala has been associated with processing of emotions, but recently also with the integration of social cues to guide decision-making and other cognitive processes.

Question 19

why can it be hard to develop treatments for cognitive symptoms of schizophrenia?

Answer 19

• cognitive impairments in schizophrenia patients comprise a large range of different cognitive processes: executive functions, working memory, language, episodic memory, processing speed, attention, inhibition and sensory processing
• This large range of cognitive symptoms makes it difficult to understand the underlying mechanisms and therefore it’s also difficult to develop effective interventions.

Question 20

Cognitive symptoms associated with schizophrenia, Barch & Ceaser (2012)

Answer 20

• Barch & Ceaser (2012) proposed the hypothesis Common mechanism across cognitive domains ’context processing’, ‘WM’ and ‘episodic memory
• They suggest that individuals with SZ show an impairment in representing goal information in WM to guide behaviour this is called proactive control
• Proactive control has been associated with a representation of information, and therefore an activation, in the dorsolateral prefrontal cortex (or DLPFC)

Question 21

Dual mechanisms of control (Braver et al., 2009)

Answer 21

• For all goal-directed behaviour, we first need to have a goal. Goals are intended outcomes of actions or mental operations.
• Goals need to be actively represented in WM before a task starts or a decision is made so that they can trigger appropriate actions or mental operations. This part of the model is what Barch & Ceaser refer to as ‘proactive control’.
• Proactive control also allows for biasing our attention, perception or motor systems in a goal-driven manner
• The goal representation then elicits an action and we can observe an outcome
• When we have completed an action, we also need the goal representation for the subsequent monitoring process. This refers to the evaluation if what we have achieved with our action, matches our intended goal. These monitoring processes have been associated with activity in medial frontal cortex areas, including the ACC.
• In case we have missed our goal, we might adjust various processes to be able to achieve the goal the next time we try

Barch & Ceaser have suggested that it’s the proactive control aspect that is impaired in individuals with schizophrenia. These individuals would need to rely more on reactive control when completing tasks.

Question 22

Association between proactive control deficits in schizophrenia and impairments in DLPFC activity, Barch & Ceaser (2012)

Answer 22

• Meta-analysis Minzenberg et al., (2009)
• fMRI studies showed reduced DLPFC activity in schizophrenia patients in tasks that require proactive control

Question 23

Meta-analysis (Dickinson et al., 2007) impairments in processing speed in patients

Answer 23

• that impairments in processing speed are relatively consistent and are associated with a large effect size.
• Processing speed in these studies was measured with Digit Symbol Coding-type of tasks. matching symbols need to be drawn below the corresponding numbers
• Participants will see a sample like in the top row here so that they know which number is associated with which symbol
• For the actual test, the participant is required to draw as many corresponding symbols as possible within a specified period of time. The more symbols you manage to draw correctly, the better is your processing speed.

Question 24

Explanation for slow processing speed in SZ patients

Answer 24

• could be a lack of integrity in patients’ white matter fiber tracts
• tracts connect different brain areas and are crucial for interactions between areas
• If these tracts don’t work optimally, information transfer between brain areas might be slower, possibly resulting in a reduced processing speed
• alternative explanation could be that the reduced processing speed is also due to working memory deficits
• keeping this information in working memory will enhance processing speed and schizophrenia patients might have more difficulties with this aspect

Question 25

Episodic memory in schizophrenia patients

Answer 25

• it has been shown in meta-analyses that memories for relational aspects between items are more impaired than memory for the items itself
• this impairment has been associated with reduced DLPFC activity, although the hippocampus might play a role here as well

example relational memory task:
- During an initial encoding phase, participants get presented with 3 different items on the screen arranged vertically
the task has 2 different conditions
- in the simple rehearsal condition, participants are being asked to remember the items and their position on the screen
- the reorder condition is about re-arranging items in your memory representation in a way that the items need to ordered according to their weight, from the lightest item on top to the heaviest at the bottom, a relation between objects needs to be created internally and represented in memory
- Individuals with schizophrenia seem to have more difficulties with this latter condition compared to control participants, which can be interpreted as deficits in relational memory
- might be due to patients not applying appropriate strategies during the encoding phase

Question 26

recollection in episodic memory in SZ patients

Answer 26

• episodic memory performance in schizophrenia patients is that when remembering items, recollection is more impaired than familiarity
• ‘recollection’ means ‘remembering exactly where you have seen or heard something’
• familiarity refers to a ‘feeling of knowing
• This finding therefore supports the hypothesis that the process of encoding items in relation to their context- that is, a form of relational memory- is disrupted in individuals with schizophrenia.

Question 27

Decision-making in schizophrenia - Motivational impairments in schizophrenia

Answer 27

• , individuals with schizophrenia often show motivational impairments when compared to healthy controls
• motivational deficits cause problems for the individual because they affect their social and occupational functioning
• currently there are no sufficiently effective treatments available for motivational impairments as the underlying mechanisms are still unclear

Question 28

Culbreth et al., (2018) : atypical effort-based decision-making may contribute to motivational impairments

Answer 28

• Effort-based decision-making refers to cognitive processes that individuals perform to estimate the physical or mental effort that will be required to obtain a desired outcome
• been shown in experimental settings that individuals with schizophrenia are less willing or motivated to exert effort to get monetary rewards
• has also been shown that this reduced effort allocation is correlated with the severity of negative symptoms.

Question 29

Decision-making in schizophrenia - Physical and mental effort

Answer 29

• Experiments requiring participants to make repeated decisions between doing a hard or easy task to gain a high/low amount of money
• individuals with schizophrenia less likely to select hard task compared to control participants.
• the likelihood of choosing the harder task correlates with negative symptom severity
• patients with more severe negative symptoms are less willing to put more effort into a task to get a higher reward
• finding could not always be replicated

Question 30

Neural correlates of effort-based decision-making

Answer 30

Structures involved in effort-based decision-making in healthy individuals:
- Medial frontal cortex/ACC
- Ventral striatum
- Dopamine systems

• in healthy individuals it has been shown that the BOLD activity in the ventral striatum and anterior cingulate cortex correlates with subjective action values
• activity in these areas increases with increasing reward value and decreases with increasing effort
• Individuals with SZ show reduced activity in the ventral striatum, the posterior cingulate and medial frontal cortex during effort-based decision-making compared to healthy controls.

an involvement of the ventral striatum and the medial frontal cortex could have been expected based on data from healthy individuals

Question 31

Factors influencing effort-based decision-making: Reward responsivity

Answer 31

• Reward responsivity = To what extent does a person enjoy the associated reward?
• If A does not enjoy cookies very much, he is less likely to start baking cookies. In contrast, if cookies were his favourite food, he will be more likely to make them.
• A hypothesis that has been suggested for individuals with schizophrenia is that patients show a reduced reward responsivity, and therefore are less likely to exert effort
• BUT: studies in the lab have shown that the self-reported levels of pleasure during the task did not differ from that of control participants
• Therefore, reduced reward responsivity seems to be an unlikely mechanism for reduced effort allocation in schizophrenia.

Question 32

Factors influencing effort-based decision-making: Anticipatory pleasure

Answer 32

• Anticipatory Pleasure: How good will the reward be when you get it? Strong anticipatory pleasure will lead to more effort to complete the task.
• Hypothesis: individuals with SZ show reduced anticipatory pleasure, thus are less motivated and less likely to exert effort
• studies have shown correlations between anticipatory please measured in self-reports and effort individuals with schizophrenia exert in a task: those who reported more anticipatory pleasure expended more effort.

Question 33

Factors influencing effort-based decision-making: Cognitive control

Answer 33

• Effort-based decision-making requires several functions that depend on intact cognitive control: Integrating decision information. Utilising representations of cost and reward; competing goals?
• Cognitive control deficit has been demonstrated in individuals with schizophrenia - associated with reduced DLPFC activity
  BUT: more robust evidence showing direct link to effort still required

Question 34

Factors influencing effort-based decision-making: Defeatist performance beliefs

Answer 34

• Individuals with schizophrenia often have negative beliefs about their ability to complete a task successfully
• if person A thinks he is not good at baking, he is less likely to attempt to do it
• belief influences precision of estimated effort (task might be a lot harder than you thought if you are not good at something)

Question 35

Factors influencing effort-based decision-making: Dopaminergic medication

Answer 35

• Effort-based decision-making associated with striatal dopamine
• Antipsychotics block dopaminergic (D2) receptor sites
• Antipsychotics might modulate activity in brain areas involved in effort-based decision-making
• Culbreth et al., D2 affinity of patient’s drug correlated
  with willingness to put effort in a task
• However: Only had small sample size and correlation confounded with negative symptom severity.