Schizophrenia- Neurobiology and treatment Flashcards
Consider the aetiology of schizophrenia
What is its penetrance?
How do hallucinations arise?
Genetic overlap with other disorders?
Partial penetrance
Polygenic multiple susceptibility genes
Genes don’t code hallucinations, they determine structural cell components. A variation in the sequence of a gene could lead to changes in interactions that cell has with other cells
Genetic overlap with autism and other neurodevelopmental disorders
Consider the aetiology of schizophrenia. Explain biological synergism as applied to it.
The concept that the interaction of environment (senses, social interaction) and biological molecules (encoded by genes) creates a summation effect that is larger than the two individual effects.
Genetic factors: susceptibility genes
Obstetric complications, prenatal infection, nutritional deficiency are environmental factors at birth that can contribute to the development of schizophrenia.
During adolescence, adverse life events and substance abuse (cannabis 6x risk) can contribute to the development of schizophrenia
Consider the neuropathology of schizophrenia.
Which structural changes occur?
- Ventricular enlargement
- Reduced brain volumes (less grey matter)
- Cytoarchitectural differences in cortex and hippocampus
***Paracingulate sulcus morphology associated with hallucinations
Consider the neuropathology of schizophrenia.
What is the neurodevelopmental model
What is the test for cognitive flexibility?
During adolescence, grey matter is lost which may speed up in early-onset schizophrenia
Grey matter is lost by
- Synaptic pruning- clean up job conventionally thought to eliminate weak synapses. In schizophrenia, pruning process hacked away indiscriminately knocking out strong synapses
- Increased myelination
= UNDER FUNCTIONING PREFRONTAL CORTEX
Test: Wisconsin Card Sorting Tast
Consider the neurophysiology of schizophrenia.
What are the functional changes that occur?
- Hypofrontality during periods of high cognitive load
- Hyper-excitable sensory cortex
- Auditory cortex activation during hallucinations (fMRI) - Abnormal neural oscillations: there are differences in neural oscillations and synchrony between controls and patients with schizophrenia
What are oscillations?
What is neuronal synchrony?
Order the types of rhythmic waves from lowest frequency to higher. What are the higher frequency waves used for? Which travel fastest?
- Oscillations: important organizers of brain activity, plasticity and connectivity. Emerge in adolescence as brain matures
- Neuronal synchrony: well-timed coordination and communication between neural populations
Theta (4-8Hz)
Alpha (10Hz)
Beta (15-30Hz)- eyes open, motor
Gamma (30-80Hz)- attention, perception, working memory
Gamma travel fastest
Consider the psychopharmacology of schizophrenia
Which pathways are implicated?
NIGROSTRIATAL SYSTEM
Mesocorticolimbic pathway - responsible for reward and reinforcement provides stimulus salience
- Includes mesolimbic and mesocortical system
Dopamine neurons are involved. Their cell bodies are in the midbrain and project into the forebrain
Consider the psychopharmacology of schizophrenia
How do typical antipsychotic drugs work?
(Neuroleptic) drugs
- D2 Receptor antagonists
- Prevent positive symptoms
- Treatment for drug-induced psychoses such as DA agonists cocaine, amphetamine and L-Dopa
What is the evidence for the glutamate hypothesis?
PCP (angel dust) causes many positive, negative and cognitive symptoms of schizophrenia
-It is an NMDA receptor antagonist
Treatment is used to model schizophrenia in animal studies:
- NMDA antagonism in prefrontal cortex means less glutamatergic firing to VTA GABA neurons
- Less GABAergic inhibition of VTA-NAcc DA neurons
- Greater DA release in NAcc
- Less activation of VTA-PFC DA neurons- less Glu- Hypofrontality
HYPOactive PFC and HYPERactive NAcc
Causes positive symptoms of schizophrenia
Describe the cognitive impairment that arises in schizophrenia
Enduring symptom of the disease
Lower IQ
Attention deficits (Stroop test)
Working memory (Wisconsin card sorting test)
Planning and information processing deficits
What are the effects of hypoactivity in Pre-frontal cortex/
Hyopfrontality leads to:
Decreased glutamate
Increased DA release in NAcc
Decreased DA in PFC
What happens as a result of NMDA receptor blockade?
Why do we not use NMDA agonists?
Positive and negative symptoms
Problems arise as difficulty in localizing effect
Will overexcite the brain–> seizures
Which monoamine do cocaine and amphetamines increase availability of?
Dopamine
Causes schizophrenic-like symptoms
Antipsychotic drugs block D2 receptors
What happens if dopamine is overly available?
What happens dopamine is less available?
Schizophrenic-like symptoms
Parkinson-like symptoms
- Parkinsons treatment increases dopamine
