-Underactivation of systems alters migration, synaptic organization and cell survival -Overactivation of systems can lead to altered synaptic connectivity and cell death
Neuropathology Structural alterations
Behavioral symptoms indicative of brain damage (unusual rates of blinking, poor control of eye movements, unusual facial expressions) Enlarged ventricles (Weinberger & Wyatt, 1982;
Cannon et al 2002
Hypofrontality
Reduced activation of the dorsolateral prefrontal cortex contributes to negative symptoms and cognitive deficits
– Functional imaging studies report reduced activation – Evidence of executive functioning deficits
Schizophrenia
What causes schizophrenia? Neuropathology
– Structural and functional changes – Neurochemical alterations
Treatments
Schizophrenia
Emil Kraepelin ―Dementia Praecox‘ (1896) Blueler ―Schizophrenia‖ Onset: adolescence or young adulthood DSM-IV review:
But why are symptoms not observed until adolescence?
Something must trigger the degenerative process at the period of adolescence Loss and disorganization of neurons become ‗unmasked‘ with pruning and synaptic reorganization
– Positive symptoms (delusions, hallucinations, disorganized speech or behavior) – Negative symptoms (catatonia, affective flattening, withdrawal, or avolition) – Social-occupational disturbance – 6+ months
DOPAMINE PATHWAYS
Basal Nucleus Ganglia accumbens Substantia nigra
a
b
c
hypothalamus
d
Tegmentum
mesolimbic pathway
mesolimbic overactivity = positive symptoms of psychosis
– Altered density and disorganization of neurons found in the white matter below layer VI in the cortex – Disorganized pyramidal cells in the hippocampus
meso-cortical pathway
Amphetamine-induced dopamine release is enhanced in schizophrenics
Laruelle et al 2003
Amphetamine-induced dopamine release produces positive symptoms
Catatonic Paranoid Disorganized
Unlikely to be a related to a single physiopathology
Neuropathology
Neurodevelopmental hypothesis Neurodegenerative hypothesis Dopamine hypothessis Glutamatergic hypothesis
dysfunction
death
toxic or genetic insult
poor neuronal migration
inadequate synapse selection
poorly innervated
Could altered development be related to glutamatergic dysfunction?
Reduced activation of the dorsolateral prefrontal cortex during a context processing/attention task in first episode/drug naï ve schizophrenics
MacDonald et al., 2005
et al, 2003)
Physical abnormalities (Schiffman, et al. 2002) Rates of concordance are higher in monochorionic twins compared dichorionic twins (60% vs. 11%) (Davis, et al, 1995)
Andreason)
Ventricular enlargement in monozygotic twin with schizophrenia
Barondes, 1993
Hippocampal volume loss and enlarged ventricles
Van Heron et al., 2005
Rapid loss of brain volume during adolescence in schizophrenics
Thompson et al, 2001
Thompson et al, 2001
Twin study—loss of dlPFC and temporal cortical tissue
1996)
Children who later become schizophrenic exhibit poor social adjustment and school performance Developmental delays Premorbid psychopathology (anxiety, depression, conduct disorders, ADHD) (Kim-Cohen
Neurodegenerative Hypothesis
SPECTRUM OF EXCITATION BY GLUTAMATE
Normal
Excess excitation - Mania - Panic
Excitotoxicity - Damage to neurons Excitotoxicity - Slow neuroathology Structural alterations (cont)
Alterations in numerous areas, including frontal lobes, medial temporal lobes, lateral temporal lobes, parietal lobe, basal ganglia, corpus callosum, thalamus and even the cerebellum White matter deficits Evidence of disorganized neurons and failures of migration
Dopamine Hypothesis
Original Formulation
– Overactivity of subcortical D2 receptors contributes to positive symptoms
Classical antipsychotics were DA D2 antagonists DA agonists induce psychotogenic effects
**These are not exclusive
What causes schizophrenia?
Heritable (Shastry, 2002)
Environmental factors
– Epidemiological studies
Birth complications Maternal stress Seasonality effect Viral epidemics Latitude effect Rh incompatibility
Altered development of hippocampal pyramidal neurons
Neurodevelopmental Hypothesis
Home movies from families with schizophrenic child displayed abnormal behavior (Walker et al, 1994;