Schizophrenia

Question 1

What are Schneider’s First Rank Symptoms

Answer 1

Delusion
Auditory hallucinations
Thought disorder; passivity of thought (withdrawal, insertion, broadcasting)
Passivity experiences (passivity of affect, passivity of impulse, passivity of volition, somatic passivity)

Question 2

Describe the hallucinations in schizophrenia

Answer 2

Auditory
Visual hallucinations very rare; typically occurs in delirium or organic causes
Occasionally tactile
Not auditory misperceptions; it sounds like real speech in external space (command hallucination)

Question 3

Describe the delusions in schizophrenia

Answer 3

Fixed rigidly held beliefs
Dominates thinking and is socially disabling
Often bizarre
Reason patient gives for belief important
Not eccentric ideas or suspicion; e.g. rigidly held belief that radio transmitter is implanted into ear

Question 4

Describe the negative symptoms associated with schizophrenia

Answer 4

Persistent loss of usual activities and interests, apathy, blunted affect, poverty of speech
Social withdrawal, impaired attention, anhedonia, lethargy

Very disabling; not responsive to antipsychotic medication
Not due to mood disorder or antipsychotic SE (by definition)

If it was due to a mood disorder the patient would have schizoaffective disorder, not schizophrenia

Question 5

Describe passivity phenomena associated with schizophrenia

Answer 5

Patients belief that they no longer control their actions, feelings or thoughts
External agent controlling them to act, feel or think

Question 6

Describe Whitford’s theory of schizophrenia

Answer 6

Brain abnormalities and abnormal salience (hallucinations and delusions) and agency (passivity phenomena)

SZ arises because of a genetic trigger (e.g. sex hormone linked) in late adolescence/ early adulthood. For example, a trigger results in abnormal expression of oligodendrocyte linked genes during pre-pubertal myelination of the associated cortices

Myelin structurally abnormal (abnormal FA) and consequently there is abnormal ability to insulate axon membranes affecting the velocity of action potentials
Functional disconnections result in disruption of corollary discharge mechanisms
Self-generated actions/ thoughts/ speech not tagged as internally generated leading to first rank symptoms with an abnormal sense of agency

If brains response to constantly experiencing internally generated events such as unexpected external events is to increase DA noise; then hyperdopmanergia could be treatable by DA blockers

Major factors in determining whether a synapse survives peri-adolescent synaptic pruning is it synchronicity with other neurons. Abnormal myelination could result in increased synaptic loss = grey matter abnormalities

Question 7

Is there a genetic link in schizophrenia when looking at adoption/ twin studies studies?

Answer 7

Yes; children of SZ mothers adopted soon after birth by non -SZ families have a 13% increase in likelihood of developing schizophrenia

There is no increased risk of developing SZ for children of non-SZ parents similarly adopted

% lifetime risk of SZ:
General pop; 2-3%
DZ twin; 16-17%
MZ twin/ both parents; 45%

Question 8

What has been the problem with genetic studies in SZ?

Answer 8

Problem with replication between studies
Multiple genes each with very small effect
Molecular genetics explain a very small amount of variance seem
Good evidence for genetic abnormalities from family/ adoption studies but molecular genetic studies have not identified clinically useful findings for drug discovery

Question 9

What white matter abnormalities are seen in SZ?

Answer 9

Biggest abnormalities in corona radiata and corpus callosum

Robust evidence for widespread white matter abnormalities

Question 10

What is the corollary discharge hypothesis?

Answer 10

Theory of normal physiological mechanism which if abnormal would lead to symptoms

Corollary discharge theory:
Motor command from cortex feeds to the motor system which then feeds to the sensory system allowing for sensory re-afference and discrepancy

Alternative efference copy sent from the motor command to the forward model which acts to predict the sensory consequence of the motor system. Prepares the sensory feedback - corollary discharge (estimated sensory feedback).

Actual sensory feedback compared with predicted feedback (corollary discharge) to inform CNS about external actions. This acts to partially cancel out self generated sensation. The prediction “tags” external actions allowing discrimination from internal actions e.g. how you know the difference between external world movement vs self-generated eye movement

Question 11

How can abnormal corollary discharge relate to the symptoms of SZ?

Answer 11

Inner speech/ thoughts are internalized - corollary discharge applies

Auditory hallucinations are due to a failure of corollary discharge connections due to impaired white matter tract integrity
From broca’s to wernickes there is a failure of connection

Auditory hallucinations are untagged sub vocal speech and therefore not recognized by the brain as self-generated

Question 12

What is the experimental evidence for abnormal corollary discharge in SZ?

Answer 12

Very few studies

Relates to difficulty with funding in psychiatric disorders

Question 13

What is passivity phenomena?

Answer 13

Experience that actions, thoughts and emotions are generated by outside agent
Means being controlled like a “robot”

Altered sense of agency in SZ hypothesised to be dysfunction of perception and action (e.g. corollary discharge mechanism) therefore faulty integration of prior knowledge and expectations with evidence

Question 14

What are the 2 separate cues to sense of agency?

Answer 14

Sensorimotor system (corollary discharge) 
Meta cognitive system (interprets cues) 

Physiological prediction deficit in sensorimotor function leads to distorted agency cues which modulates cognitive levels

Question 15

How was this sense of agency and passivity phenomenon being related to abnormal corollary discharge and cognitive system tested?

Answer 15

Studying experimentally different timing cues to agency

Agency requires causal relationship; action precedes sensory and perceptual events

Subjects listened to a computer generated simple auditory sequence and reproduce it
Whilst reproducing there was 2 randomly ordered sound reproduction conditions;
1) self control; heard own undistorted tapping
2) external control; heard distorted different tapping
Asked if what they heard was self-produced or not

SZ pts tended to over-attribute auditory events to own actions
Tendency to attribute sensory events to own action most highly correlated with highest self ratings of clinical passivity phenomena

OPPOSITE of what was hypothesized

Interpreted to reflect secondary cognitive compensatory could explain this.

Question 16

What experimental data is there to show that SZ patients are associated with a specific impairment of the predictive component mechanisms?

Answer 16

Voss; experiments as well as clinical observations show an enhanced rather than reduced sense of agency
Patients had to discriminate between predictive and retrospective mechanisms
Showed those with SZ have a specific impairment of prediction

Question 17

Is there a link between action and effect?

Answer 17

Yes
Predictively (Action predicted to generate a given effect) - corollary discharge 
Retrospectively (inference action caused effect - cognitive mechanism)

Question 18

What is intentional binding?

Answer 18

Linkage with external effect - provides an implicit measure of the sense of agency. Has both predictive and retrospective components

For example, when key press is frequently followed by a tone; healthy subjects perceived the time of action shifted towards the anticipated tone, even when there was no tone delivered suggesting it was predicted
Shift in action awareness also occurred when the tone was not highly predictable but occurred, suggesting retrospective inferential processes

Question 19

Describe the difference seen with predictive and retrospective components in intentional binding between controls and SZ

Answer 19

Controls; strong predictive component of intentional binding with minimal retrospective component

SZ; absent predictive component with strong retrospective component (postdiction)

Higher incidence of first rank sy, such as delusions and hallucinations are associated with a more reduced predictive component

Positive sy occur because the comparator lacks a predictive input. Even internally generated info such as ones own thoughts and intentions would be perceived as originating externally

Question 20

What is a key mechanism underlying the sense of agency in SZ?

Answer 20

Association between ones action and external effect
Association is the experience of fluently controlling actions and external world

Such associations produce normal systematic distortions of time perception linked to voluntary action

Patients were generating imprecise predictions rather than no predictions
The strength of outcome prediction was not related to objective likelihood of the outcome predictions were equally strong in high and low probability conditions (implying aberrant DA signalling)

Question 21

Are there any links between DA function and intentional binding?

Answer 21

Drug withdrawal study on patients with PD
PD off meds; same intentional binding
PD on meds; increased intentional binding

Associative learning paradigm modified blocking paradigm prediction error signals

Learning is only when there is unexpected high surprise events; increased intentional binding effect negatively correlated with schizotypy ratings

Question 22

What is the brains response to constant internally generated internal events as unexpected external events?

Answer 22

Hyperdopaminergia

Disrupted oligodendrocyte growth in mice with reported hyperdopaminergia

Question 23

What DA system is a critical component of sailence?

Answer 23

Mesolimbic DA

Psychosis is a state of aberrant salience

Question 24

What is salience?

Answer 24

Process by which events and thoughts grab attention, and influence goal directed behaviour because of association with reward or punishment linked to concepts of value

Question 25

What is the link of delusions and hallucinations with salience?

Answer 25

Delusions; beliefs with extremely high abnormal salience

Hallucinations; abnormal high salience of internal thoughts

Question 26

What nT mediates salience acquisition and expression?

Answer 26

DA but it does not create the process; DA release is dependent on external stimuli which the DA system responds to to then modify the brain

Question 27

What is the link of psychosis with DA?

Answer 27

Dysregulated DA transmission leading to stimulus independent release of DA

Dysregulated DA firing becomes a creator of “abnormal saliences” (psychotic symptoms)

Question 28

How do antipsychotics work in linkage with salience?

Answer 28

Efficacious because they all share a common property of dampening DA function and therefore dampening salience (abnormal and normal)

Common psychological effect of antipsychotics is to dampen salience acquisition

Provide a physiological context of attenuated salience; reinforcement of importance or value of events

Question 29

What is punishment avoidance associated with?

Answer 29

Indirect basal ganglia pathway and D2 receptors

Reward-learning is associated with direct basal ganglia pathway and D1 receptors

Question 30

Do antipsychotics remove psychotic symptoms?

Answer 30

No; they attenuate the salience of distressing ideas and percepts over time
Attenuation of normal salience may in part account of the negative symptoms; antipsychotics do not treat these

Question 31

What does the clinical efficacy of antipsychotic drugs rely on?

Answer 31

Ability to block D2 receptors; and therefore the indirect basal ganglia pathway

Question 32

Is there instant uptake of antipsychotics into the basal ganglia?

Answer 32

No; it will occupy D2/3 receptors in a dose dependent manner

Question 33

Describe the medication given in SZ and the downfalls associated with it

Answer 33

Antipsychotics; dopamine D2 blockade; positive symptoms
5-25%; unresponsive
5-10% intolerant (parkinsonism, akathisia, dyskinesia)
40-60%; non-compliant with oral meds

Depot; increased compliance, reduction in relapse rates

Continuous therapy far better than intermittent treatment

Question 34

Traditional vs atypical?

Answer 34

Traditional; chlorpromazine, haloperidol

Atypical; clozapine, olanzapine, risperidone, quiteiapine

Question 35

When is clozapine prescribed?

Answer 35

Failure to respond to 3 antipsychotics using an adequate dose for an adequate duration

Agranulocytosis; regular FBC required

Question 36

Are there reliable predictors of outcome in SZ?

Answer 36

No; heterogenous disorder
Most pts become progressively and severely disabled

Chemical factors assoc with good prognosis:
Female, abrupt onset of illness, married, good premorbid social adjustment
FMHx of affective disorder, short duration of illness prior to tx
Good initial response to treatment, lack of neg sy, lack of cognitive impairment
No ventricular enlargement

Question 37

When is the rates of suicide highest in SZ?

Answer 37

10%
Early in illness, males with chronic illness, tardive dyskinesia, unemployed
Previous high educational attainment, sudden stoppage of meds
Recent discharge from hospital

Question 38

What causes the grey matter abnormalities seen in SZ?

Answer 38

Neutrophil elimination (not neuronal death) 
Most likely loss of dendritic abors and associated synaptic infrastructure 
Progressive over initial years of illness

Question 39

What grey matter abnormalities have been observed in SZ brains?

Answer 39

Reduction in hippocampal volumes (similar to depression)
Amygdala
Thalamus
N. Acc