神经病理学

Neurodegenerative Hypothesis
SPECTRUM OF EXCITATION BY GLUTAMATE
Normal
Excess excitation - Mania - Panic
Excitotoxicity - Damage to neurons Excitotoxicity - Slow neurodegeneration
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)
Neuropathology 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
Catatonic Paranoid Disorganized
Unlikely to be a related to a single physiopathology
Neuropathology
Neurodevelopmental hypothesis Neurodegenerative hypothesis Dopamine hypothessis Glutamatergic hypothesis
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;
Reduced activation of the dorsolateral prefrontal cortex during a context processing/attention task in first episode/drug naï ve schizophrenics
MacDonald et al., 2005
1996)
Children who later become schizophrenic exhibit poor social adjustment and school performance Developmental delays Premorbid psychopathology (anxiety, depression, conduct disorders, ADHD) (Kim-Cohen
– Altered density and disorganization of neurons found in the white matter below layer VI in the cortex – Disorganized pyramidal cells in the hippocampus
Laruelle et al, 1996
Increased dopamine releaபைடு நூலகம்e in medication-naï schizophrenic ve patients
Hietala, et al. 1995
D2 receptors?
Mixed data Some find no differences Others find moderate increases (Kestler et al., 2001) What about D3 and D4 receptors?
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
Associated Features
Cognitive Disturbances
– Memory – Sensory filtering – Attention – Emotion recognition – Eye-tracking
Interpersonal Dysfunction
Subtypes
**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
DOPAMINE PATHWAYS
Basal Nucleus Ganglia accumbens Substantia nigra
a
b
c
hypothalamus
d
Tegmentum
mesolimbic pathway
mesolimbic overactivity = positive symptoms of psychosis
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
Excitotoxicity - Catastrophic neurodegeneration
excitation
Could the psychotic symptoms themselves be producing additional excitotoxicity?
Neurochemical Alterations
-Underactivation of systems alters migration, synaptic organization and cell survival -Overactivation of systems can lead to altered synaptic connectivity and cell death
Andreason)
Ventricular enlargement in monozygotic twin with schizophrenia
Barondes, 1993
Hippocampal volume loss and enlarged ventricles
Van Heron et al., 2005
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
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:
meso-cortical pathway
Amphetamine-induced dopamine release is enhanced in schizophrenics
Laruelle et al 2003
Amphetamine-induced dopamine release produces positive symptoms
– Positive symptoms (delusions, hallucinations, disorganized speech or behavior) – Negative symptoms (catatonia, affective flattening, withdrawal, or avolition) – Social-occupational disturbance – 6+ months
pure D2 blocker
11-2
Stahl S M, Essential Psychopharmacology (2000)
Re-formulation of dopamine hypothesis
Imaging studies indicate loss of tissue in the frontal lobes as well as reduced activation Deficit in activation of D1 receptors in the prefrontal cortex contributes to negative symptoms and cognitive deficits
Altered development of hippocampal pyramidal neurons
Neurodevelopmental Hypothesis
Home movies from families with schizophrenic child displayed abnormal behavior (Walker et al, 1994;
dysfunction
death
toxic or genetic insult
poor neuronal migration
inadequate synapse selection
poorly innervated
Could altered development be related to glutamatergic dysfunction?