neuronal mechanisms in schizophrenia robert freedman, m.d. department of psychiatry university of...
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Neuronal Mechanisms in Schizophrenia
Robert Freedman, M.D.
Department of Psychiatry
University of Colorado
Denver, Colorado
Schizophrenia
• 1% affected, onset generally late adolescence to early adulthood
• Auditory hallucinations and paranoid delusions are the most common forms of thought disorder, the most characteristic chronic symptom
• A decrement in psychosocial function, often called “negative symptoms” is part of the illness
Sensory Gating Disturbance
• “My mind has to be here, it has to be there, it has to be everywhere. I can’t concentrate on anything.”
• “When he gets ill, his sense of hearing seems to increase. He hears the neighbors across street arguing.”
The decrease of nicotinic receptors on nerve cells means that the brain’s own acetylcholine is no longer sufficient to
activate the neurons that filter out noises
fMRI indicates increased hemodynamic activity in the hippocampus in schizophrenia during smooth pursuit eye movements
…even though uninterested and autistically encapsulated patients pay little attention to the outside world, they register a remarkable number of events of no concern to them. The selection which attention exercises over normal sensory impressions may be reduced to zero, so that almost everything that meets the senses is registered. Thus both the facilitating and inhibitory propensities of attention are disordered. Bleuler, 1911
Grandfather—Chronically Insane
Father—Committed Suicide
Proband--- Philosopher Arthur Schopenhauer
“The amount of noise which anyone can bear undisturbed stands in inverse proportion to his mental capacity….Noise is a torture to all intellectual people.”
The decrease of nicotinic receptors on nerve cells means that the brain’s own acetylcholine is no longer sufficient to
activate the neurons that filter out noises
A. Control female, -86 C/C
T/C= 0.14
B. Control female, -86 C/T
T/C= 0.60
Conditioning Testing
P50
C. Schizophrenic female, -86 C/T
T/C= 0.54
50 ms
4V
1-Dopamine adjusts the volume
2-Acetycholine and GABA filter signal from noise
3-Glutamate imprints new memories
1-Dopamine adjusts the volume—Blocked by antipsychotic
2-Acetycholine and GABA filter signal from noise
3-Glutamate imprints new memories
Clozapine, a drug used to treat schizophrenia, increases acetylcholine and normalizesinhibition; cigarette smoking drops by 50%
The University of Colorado with NARSAD, Stanley, and NIMH and VA support, is developing new drugs to treat schizophrenia and bipolar disorder by targeting nicotinic
receptors.
1-Dopamine adjusts the volume
2-Acetycholine and GABA filter signal from noise
3-Glutamate imprints new memories
Memory disorder in schizophrenia• Decreased ability to learn efficiently• Poverty of content• Persistence of paranoid memory
• Malfunction of NMDA and other glutamate receptors
• Decreased volume of brain regions critical to cognition
• Diminished extinction
Genetics, Neurobiology, and Our Conception of Schizophrenia
• Schizophrenia used to be conceptualized as a rare, disastrous malfunction of the mind and/or brain, depending on your view of Cartesian dualism
• If three independent factors are involved, then an application of Mendel’s second law suggests that for a population prevalence of schizophrenia = 0.01, the prevalence of any one of these factors is 0.011/3 = 0.22. Calculate the probability that you have at least one factor. What might its effect be on your mental function?