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Transcript of Neurodevelopment NEW
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NEUROBIOLOGY
INTRODNAGENES5-HTDOPABRAIN12043ATOMAUT3
DOPAMINE
DOPAMINE
B.L. CONDE, MD, FPPA, FPNA
The Neurodevelopmental
Theory of Psychopathology in
Schizophrenia
UST
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The lifetime risk for schizophrenia correlated with genetic relatedness
1%
2%
2%
4%
5%
6%
6%
9%
13%
17%
48%
0% 10% 20% 30% 40% 50% 60%
None (General Population)
First Cousin
Uncle/Aunt
Nephew/Niece
Grandchild
Half sibling
Parent
Sibling
Child
Dyz Twin
Mono TwinGenes shared100%50% (first-degreerelatives)
25% (second-degreerelatives)12.5% (third-degreerelatives)
Genes shared100%50% (first-degreerelatives)
25% (second-degreerelatives)12.5% (third-degreerelatives)
Relationship to schizophrenic individual
Adapted from Gottesman 1991
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NEUROBIOLOGY
INTRODNAGENES5-HTDOPABRAIN12043ATOMAUT3
DOPAMINE
DOPAMINE
The MIND &BRAIN DICHOTOMY
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NEUROBIOLOGY
INTRODNAGENES5-HTDOPABRAIN12043ATOMAUT3
DOPAMINE
DOPAMINE
BIOLOGICAL vsPSYCHOLOGICAL
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The Basis of Contemporary Neural Science
All mental processes are biological and any alteration in those processes is organic
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Questions
1. How do the biological processes of the brain give rise to mental events ?
2. How do social factors modulate the biological structure of the brain ?
3. To what degree is this biological process determined by genetic and developmental factors ?
4. To what degree is it environmentally or socially determined ?
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NEUROBIOLOGY
INTRODNAGENES5-HTDOPABRAIN12043ATOMAUT3
DOPAMINE
DOPAMINE
GENES vs
ENVIRONMENT
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NEUROBIOLOGY
INTRODNAGENES5-HTDOPABRAIN12043ATOMAUT3
DOPAMINE
DOPAMINE
The genetic blueprint are coded in the DNA, yet the blueprints are modified and shaped by environmental influences that the brain/mind encounter in a person’s journey through life.
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The
NEURODEVELOPMENTAL HYPOTHESIS
of schizophrenia proposes that a proportion
of schizophrenia is the result of an early brain
insult, either pre or perinatal which affects
brain development leading to abnormalities which are
expressed in the adult brain
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Neurodevelopmental hypothesis of schizophrenia suggests that genetics and/or epigenetic events that occur during critical periods of neuronal
growth may negatively influence brain development
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A meta-analysis of 40 MRI studies described the following
abnormalities in Volume reduction
Whole brain (3%) Temporal lobes (left – 6 %, right
9.5%) Amygdala/Hippocampal complex (left – 6.5%, right 5.5%)
Volume is increased in the lateral ventricles(left – 44%, right - 44%)
Gray matter is reduced but white matter volumes maybe increased
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Retrospective data provide evidence that women in their 2nd trimester (not
1st or 3rd) of pregnancy have an increased risk of offsprings developing schizophrenia
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Neuropathological data from brain tissue in schizophrenia suggest that a subgroup of schizophrenia may have disturbances related to 2nd trimester
neuronal development
Arnold & Trojanowski, 1996Burney et al, 1995Chua & Murray, 1996Jacob & Beckmann, 1986Kovelman & Scheibel 1984Weinberger, 1995
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Aberrant expression of developmental and plasticity-associated markers (NCAM 9 GAP-43)
Aberrant expression of developmental and plasticity-associated markers (NCAM 9 GAP-43)
Sulcal-gyral abnormalities have been reported in some post-mortem studies of schizophrenic brains.
Sulcal-gyral abnormalities have been reported in some post-mortem studies of schizophrenic brains.
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Anatomical Evidence That May Support a
Neuro-Developmental Defect
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1. Ventricular enlargement in schizophrenia may be indicative of a more serious form of illness
a. Poor neuropsychological test (Johnstone et al, 1976)
b. Treatment resistant (Weinberger et al, 1980)
c. More negative symptoms (Arderlasen et al, 1982)
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2. Hippocampusa. Finding of cellular architectural disarray
(Kovelman & Scheibel,
1984)
b. Decrease in neuronal volume(Heckers et al,
1991)
c. Reduction in pyramidal cell density (Jeste & Lohr,
1989)
d. Decreases in neuronal sign in subiculum & CA1 (Arnold et al,
1995)
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They are present in both newly diagnosed as well
as chronic schizophrenics
They appear to be non-progressive
Cognitive deficits found in schizophrenia show no
deterioration over the course of the illness
These suggest a neurodevelopmental process rather than a
neurodegenerative one because:
These suggest a neurodevelopmental process rather than a
neurodegenerative one because:
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Gliosis
• Is the neural scarring following brain lesions other than those that occur early in neurodevelopment
• Characteristic of neurodegenerative disorder
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Relative lack of evidence for neurodegenerative defect in schiziphrenia
Measurement of gliosis indicative of neurodegeneration in brain tissue fail
to demonstrate that neurodegeneration plays a role
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There is NO extensive gliosis seen in brains of schizophrenic patients
There is failure to develop normal cerebral asymmetries, which are normally formed during the second trimester of pregnancy
Pathological changes appear to affect the left side of the brain more severely than the right.
Pathological changes appear to affect the left side of the brain more severely than the right.
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Psychotic Relapses and Progressive
Neurodegeneration• Several MRI follow-up studies since 1995 were
done in first-episode psychosis and after subsequent psychotic relapses
• Findings include:• 1) brain volume (about 1-2% after each relapse)• 2) ventricular size• 3) frontal lobe volume• 4) temporal lobe volume• Extensive and widespread cortical tissue loss was
also reported after psychosis in adolescents
Nasrallah HA. 2002.
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MRI of Ventricular System
Nasrallah HA. 2002.
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Multiple Relapses May Lead to Continuing Neurodegeneration
• Deterioration in schizophrenia is probably the result of neurodegeneration
• Many patients who stop treatment and then relapse fail to regain prior level of function
• Early intervention is key• Antipsychotics may improve long-term outcome by
counteracting neurodegenerationReferences: Lieberman JA, et al. J Clin Psychiatry1996;57(suppl 9) 5-9. Sheitman BA, et al. Psychiatric Res. 1998:32:143-150.
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Compelling evidences come from studies of cytoarchitecture which demonstrated that neurons among schizophrenic brains were
MISPLACED,
MIS-SIZED and
DISORGANIZED.
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The Premorbid Child
If schizophrenia is caused by an
aberration in the developing brain, then
it is reasonable to expect the presence
of some subtle abnormalities of
neural function and developmental
anomalies in early life.
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It is hypothesized that genetic defects predispose the brain to be affected by intrauterine or perinatal environmental events.
It is hypothesized that genetic defects predispose the brain to be affected by intrauterine or perinatal environmental events.
Alternatively, genetic control of brain development maybe disrupted by adverse environmental events.
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The Premorbid Child
• Higher incidence of neuromotor abnormalities
• Delayed developmental milestones
• Behavioral & intellectual abnormalities
• Within 1st 2 year, reduced responsiveness, less positive affect, less eye contact
• 75% “soft” neurological signs – abnormal gait, disgraphaesthesia, tics, twitches
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Mechanisms of Delayed Onset
• After peaking during childhood, synaptic density in human frontal cortex decline by 30-40% by adulthood
– Selective neuronal death– Progressive synaptic elimination
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Mechanisms of Delayed Onset
Maldevelopment in utero sets the stage for secondary disorganization in
adolescence
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Mechanisms of Delayed Onset
The lesions remain dormant until normal brain maturation in
adolescence leads to the use of neuronal circuits that are poorly
developed in children
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Mechanisms of Delayed Onset
In humans, myelination in circuitry to or from hippocampus is only complete in
adolescence
Clare HoltmanApril 2000
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First Episode Schizophrenia
• Enlargement of ventricular system
• Reduction of total brain size
• Reduction of hippocampal size
• No reduction of temporal lobe or amygdala volumes
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International researcher from USA, UK, and Australia reported longitudinal
temporal horn lengthening and abnormalities in paracingulate sulcus
asymmetry in 2 studies among adolescents with schizophrenia
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Canadian study found significantly lower total gray matter volumes in 17 young schizophrenia patients (mean
age 20 years) compared to 16 healthy controls
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etiological Factors
Risk factors:Nutrition
Seasonality
Infection or infectious
agents
Obstetric complications
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4 lines of evidence support prenatal nutritional deficiencies or a plausible set of risk factors for
SCHIZOPHRENIATheir effects are not
incompatible with the epidemiology of schizophrenia
They have adverse effects in brain development
General malnutrition results in neurological anomalies of brain regions implicated in schizophrenia
Prenatal malnutrition affects maternal systems critical to the developing fetal nervous system
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NEUROBIOLOGY
INTRODNAGENES5-HTDOPABRAIN12043ATOMAUT3
DOPAMINE
DOPAMINE
NATURE VS
NURTURE
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A Synthetic Model for the Development of Mental
Illness
CAUSESMULTIPLE INTERACTING FACTORS
GENESGENES
GENE EXPRESSION
GENE EXPRESSION
VIRUSESVIRUSES
TOXINSTOXINSNUTRITIONNUTRITION
BIRTH INJURYBIRTH INJURY
PERSONALEXPERIENCES
PERSONALEXPERIENCES
Andreasen, NC: Brave New Brain. P36, 2001
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A Synthetic Model for the Development of Mental
Illness
CAUSESMULTIPLE INTERACTING FACTORS
GENESGENES
GENE EXPRESSION
GENE EXPRESSION
VIRUSESVIRUSES
TOXINSTOXINSNUTRITIONNUTRITION
BIRTH INJURYBIRTH INJURY
PERSONALEXPERIENCES
PERSONALEXPERIENCES
Andreasen, NC: Brave New Brain. P36, 2001
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A Synthetic Model for the Development of Mental
Illness
CAUSESMULTIPLE INTERACTING FACTORS
BRAIN STRUCTURE AND FUNCTIONe.g., brain development and degeneration, plastic changes
in response to experience, brain chemistry, changes inresponse to medications, changes in response to
psychotherapy
Andreasen, NC: Brave New Brain. P36, 2001
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A Synthetic Model for the Development of Mental
Illness
CAUSESMULTIPLE INTERACTING FACTORS
BRAIN STRUCTURE AND FUNCTION
MIND FUNCTIONSe.g., memory, emotion, language, attention, arousal, consciousness
Andreasen, NC: Brave New Brain. P36, 2001
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A Synthetic Model for the Development of Mental
Illness
CAUSESMULTIPLE INTERACTING FACTORS
BRAIN STRUCTURE AND FUNCTION
MIND FUNCTIONS
THE UNIQUE PERSON IN A SPECIFIC SOCIAL WORLDe.g., individual behavior and response in a specific
personal and social environment
Andreasen, NC: Brave New Brain. P36, 2001
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A Synthetic Model for the Development of Mental
IllnessCAUSES
MULTIPLE INTERACTING FACTORS
BRAIN STRUCTURE AND FUNCTION
MIND FUNCTIONS
THE UNIQUE PERSON IN A SPECIFIC SOCIAL WORLD
A SPECIFIC MENTAL ILLNESSe.g., schizophrenia, mood disorders, dementias, anxiety disorders
Andreasen, NC: Brave New Brain. P36, 2001
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Single Cell• How does a single cell, the fertilized egg, give rise to each of the differentiated cell types comprising the nervous system?
The nervous system begins to develop late in the process of embryogenesis
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EmbryogenesisEndoderm – innermost layer gives
rise to the gut, lungs and liver
Mesoderm – the middle layer, gives rise to connective tissue, muscles and the vascular system
Ectoderm – the outer most later, gives rise to the CNS and PNS
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The initial step in the development of neuronal tissue is the induction of the neural plate.
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Once cells of the neural plate are induced, they rapidly acquire specialized properties that depend on the position they initially occupy within the neural plate
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Once cells of the neural plate are induced, they rapidly acquire specialized properties that depend on the position they initially occupy within the neural plate
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Once cells of the neural plate are induced, they rapidly acquire specialized properties that depend on the position they initially occupy within the neural plate
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• The fate of the induced neural cells is controlled by 2 independent signaling systems:– Medial to lateral axis which
eventually becomes the dorso-ventral axis of the neural tube
– Antero-posterior axis that divides the neural tube into its four-region rosto-caudal subdivision
1
2
3
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1
2
3
• The fate of the induced neural cells is controlled by 2 independent signaling systems:– Medial to lateral axis which
eventually becomes the dorso-ventral axis of the neural tube
– Antero-posterior axis that divides the neural tube into its four-region rosto-caudal subdivision
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Stages of Development• Neuronal formation
• Neuronal proliferation
• Proliferation of dendrites and spines
• Synaptogenesis
• Myelination
• Pruning
• Apoptosis
Andreasen, NC: Brave New Brain. P45, 2001
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Neuronal Fate in the Mammalian Cortex
The neurons of the cerebral cortex are generated in the ventricular zone, an epithelial layer of progenitor cells that line the ventricular wall.
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Neuronal Fate in the Mammalian Cortex
Once they have left the cell cycle, the immature neurons migrate out of the ventricular
zone to form the cortical plate, which eventually becomes the
gray matter of the cerebral cortex
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Once they have left the cell cycle, the immature
neurons migrate out of the ventricular zone to form the
cortical plate, which eventually becomes the
gray matter of the cerebral cortex
Neuronal Fate in the Mammalian Cortex
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Neuronal Fate in the Mammalian Cortex
Once they have left the cell cycle, the immature neurons migrate out of the ventricular
zone to form the cortical plate, which eventually
becomes the gray matter of the cerebral cortex
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G1 S G2 M
Neuronal Fate in the Mammalian Cortex
The plane of division of
progenitor cells in the
ventricular zone influences their
fate
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G1 S G2 M
Neuronal Fate in the Mammalian Cortex
The plane of division of
progenitor cells in the ventricular
zone influences their fate
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G1 S G2 M
Neuronal Fate in the Mammalian Cortex
The plane of division of
progenitor cells in the ventricular
zone influences their fate
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G1
S
M /
G2
Neuronal differentiation does not stop when a cell leaves the cell cycle and migrates to its final position.
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For a mature neuron to participate in neuronal circuitry, it must express many specialized properties, the most important being a chemical transmitter that permits the cell to signal to other neurons.
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Rita Levi-Montalcini observed that death of neurons is a normal occurrence during embryonic development.
TARGET CELL OF NEUROTROPHIC FACTOR
TARGET CELL OF NEUROTROPHIC FACTOR
NEUROTROPHIC FACTOR HYPOTHESIS
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Stages of Development
• Neuronal formation
• Neuronal proliferation
• Proliferation of dendrites and spines
• Synaptogenesis
• Myelination
• Pruning
• Apoptosis
Andreasen, NC: Brave New Brain. P45, 2001
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The two most plausible developmental processes which may help explain the subplate marker disturbances are defects in either neuronal migration or programmed cell death
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Deprivation of neurotrophic factors activates a cell death program in neurons
TARGET CELL OF NEUROTROPHIC FACTORTARGET CELL OF NEUROTROPHIC FACTOR
NEUROTROPHIC FACTOR HYPOTHESIS
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Guidance of Axons to their Targets
Paul Weiss proposed that proper connections survive because they are the ones in which the axons and target match patterns of electrical activity
Paul Weiss proposed that proper connections survive because they are the ones in which the axons and target match patterns of electrical activity
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Guidance of Axons to their Targets
Roger Sperry, a student of Weiss, forwarded the CHEMOSPECIFICITY HYPOTHESIS
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The cellular environment provides a complex set of commands to the growing
axon.
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Axons of retinal ganglion cells follow a complex path to the optic
tectum
21
34
56
7
8
9
10
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TARGET ZONE
TECTUM
The Guidance of Axons to their Targets
Axons from the retina terminate and arborize to their termination site in the tectum
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AXONAL ENTRY
The Guidance of Axons to their Targets
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AXONAL EXTENSION
The Guidance of Axons to their Targets
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The Guidance of Axons to their Targets
AXONAL CORRECTION
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The GROWTH CONE is a sensory-motor structure that regenerates and responds to guidance cues:
In 1890s, Santiago Ramon y Cajal, the greatest of all developmental neurobiologists, proposed that the growth cone was responsible for axonal path finding
In 1890s, Santiago Ramon y Cajal, the greatest of all developmental neurobiologists, proposed that the growth cone was responsible for axonal path finding
Elongating axons terminate in a protuberance called the GROWTH CONE.
Elongating axons terminate in a protuberance called the GROWTH CONE.
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++++++
+++ ++ ++
+++ ++ ++++ +
+
+++++
+
+
++
++++
++++ ++
+++ +
+
++
--- - -- -
--- -
----
-
---
---
----
-
----------
------
---
---- - -
-
++
++
--
--
Extracellular Matrix Adhesion
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++++++
+++ ++ ++
+++ ++ ++++ +
+
+++++
+
+
++
++++
++++ ++
+++
++
++
--- - -- -
--- -
----
-
---
---
----
-
----------
------
---
---- - -
-
++
++
--
--
Cell Surface Adhesion
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++++++
+++ ++ ++
+++ ++ ++++ +
+
+++++
+
+
++
++++
++++ ++
+++
++
++
--- - -- -
--- -
----
-
---
---
----
-
----------
------
---
---- - -
-
++
++
--
--
Pioneer Neuron
Fasciculation
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++++++
+++ ++ ++
+++ ++ ++++ +
+
+++++
+
+
++
++++
++++ +
+++
+
++
--- - -- -
--- -
----
-
---
---
----
-
----------
------
---
---- - -
-
++
++
--
--
++++++
+++ ++ ++
+++ ++ ++++ +
+
+++++
+
+
++
++++
++++ +
+++
+
++
Chemoattraction
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--
--
++++++
+++ ++ ++
+++ ++ ++++ +
+
+++++
+
+
++
++++
++++ +
+++
+
++
--- - -- -
--- -
----
-
---
---
----
-
----------
------
---
---- - -
-
++
++
--
--
Contact Inhibition
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--
-++++++
+++ ++ ++
+++ ++ ++++ +
+
+++++
+
+
++
++++
++++ +
+++
+
++
--- - -- -
--- -
----
-
---
---
----
-
----------
------
---
---- - -
-
++
++
-
--- - -- -
--- -
----
-
---
---
----
-
----------
------
---
---- - -
-
Chemorepulsion
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Compelling evidences come from studies of cytoarchitecture which demonstrated that neurons among schizophrenic brains were
MISPLACED,
MIS-SIZED and
DISORGANIZED.
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Functional Hypothesis for Schizophrenia
Etiology
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Hyperdopaminergic state in subcortical area may underlie the positive symptoms of schizophrenia -
Davis, et al, 1991Davis, et al, 1991
DOPAMINE HYPOTHESIS
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Neuroanatomical Model of Schizophrenia: Prefrontal Inhibition
PREFRONTAL CORTEX
LIMBIC AREAS
SCHIZOPHRENIA
(-)
(-)
PREFRONTAL CORTEX
LIMBIC AREAS
NORMAL STATE
(-)
(-)
Brainstem Dopaminergic neurons
Adapted from Weinberger, 1987
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Hypodopaminergic state
in cortex may underlie
the negative symptoms of schizophrenia -
Davis, et al, 1991Davis, et al, 1991
DOPAMINE HYPOTHESIS
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The Four Major Dopaminergic Tracts in the Brain
MESOCORTICAL SYSTEM? Involved in the NEGATIVE symptoms ofSchizophrenia
MESOLIMBIC SYSTEM? Involved in the POSITIVE symptoms ofSchizophrenia
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Functional Neuroanatomy of Hallucinations in
Schizophrenia
INFERO-TEMORALCORTEX
VENTRAL ANTERIORMAGNOCELLULARDIVISION OF THETHALAMUS
SUBSTANTIANIGRA
PUTAMEN
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Dopaminergic Model of Psychosis
• Psychostimulant psychosis results with increasing doses of amphetamines over prolonged use.
Ellinwood, 1967; Post, 1980
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Dopaminergic Model of Psychosis
• Psychostimulant psychosis results with increasing doses of amphetamines over prolonged use.
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Dopaminergic Model of Psychosis
• Initial effects are1. Euphoria
2. Enhanced attention
3. Psychomotor agitation
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Dopaminergic Model of Psychosis
• On repeated exposure, there are1. Perceptual changes
2. Suspiciousness
3. Repetitive behavior
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Dopaminergic Model of Psychosis
• Chronic use leads to:1. Dysphoria
2. Paranoid delusions
3. Increased distractability
4. Ideas of reference
5. Auditory, visual, tactile hallucinations
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Dopaminergic Model of Psychosis
The key characteristic of psychostimulant psychosis is sensitization, inducing cross-
sensitization with other drugs or environmental stressor.
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• Kalivas, in 1995, showed that sensitization is associated with increased stimulant-induced dopamine release in the axon terminals.
• This appears to be a glutamate-dependent process involving both NMDA and non-NMDA receptors.
Dopaminergic Model of Psychosis
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• Evidences:
• Post-WW II abuse of methamphetamines
• Lieberman et al, in 1987, noted that psychostimulant-naïve schizophrenics become worse when taking psychostimulants.
Dopaminergic Model of Psychosis
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Sensitization is a function of regulatory abnormalities within the cortico-striato-thalamic circuitry.
Dopaminergic Model of Psychosis
Carlsson & Carlsson, 1990, Kalivas, 1995
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The Serotonin Hypothesis
• 5-HT projections inhibit DA at two levels:– At the midbrain, 5-HT inhibits the firing of
DA cells from the substantia nigra– At the cortex and striatum, 5-HT inhibit
synaptic release of DA
Kapur and Remington, 1996
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Serotonergic Model of Psychosis
• In 1954, Gadduan observed LSD-induced psychosis that showed some similarity to 5-HT. This was the first indication of a link between a specific neurotransmitter and psychosis
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Serotonergic Model of Psychosis
• LSD demonstrated partial agonist effect on 5-HT2A receptors
• Mark and Aghajanian, 1996
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Serotonergic Model of Psychosis
• 5-HT2A receptors, which mediate hallucinogenic effects play modulatory roles within local cortical circuits.
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The Role of Glutamate
• Glutamate communicates with two receptors: AMPA and NMDA
• LTP is enhanced by glutamate activation of NMDA receptors.
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Glutaminergic Model of Psychosis
• Luby in 1959 proposed the “phencyclidine model” of psychosis
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Glutaminergic Model of Psychosis
• Effects of PCP and ketamine are amply similar to schizophrenia
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Glutaminergic Model of Psychosis
• Rosembaum et al, in 1959, Cohen et al, 1962 compared LSD and PCP cognitive effects in healthy subjects compared to schizophrenics.
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Phenomenology of the Model Psychoses
Adapted from Andreasen, 1995
Signs/ Symptoms
5-HT Hallucinogens
Psycho-stimulants
NMDA
AntagonistsPsychotic Symptoms
Delusions
Hallucinations
Others
+
++
++
++
+
0
+
+
++Negative Symptoms
Blunted affect
Withdrawal
Anhedonia
+
+
-
-
-
-
++
++
-
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Phenomenology of the Model Psychoses
Adapted from Andreasen, 1995
Signs/ Symptoms
5-HT Hallucinogens
Psycho-stimulants
NMDA
Antagonists
Disorganization
Thought d/o
Abstraction
Attention
Reduced PPI
+
0
+
+
+
0
+
+
++
++
+
+Others (impaired)
Working memory
Declarative memory
Eye movement
Executive functions
?
+
?
+/-
?
+/-
?
+/-
+
++
+
++
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Glutaminergic Model of Psychosis
• Amphetamine-produced paranoia psychosis are associated with relative sparing of cognitive and thought disorder
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Glutaminergic Model of Psychosis
• NMDA antagonist psychosis is associated with disorganized thought and behavior, impaired cognitive function and negative symptoms.
• This closely parallels the undifferentiated and disorganized subtypes of schizophrenia.
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Glutaminergic Model of Psychosis
• Paranoid schizophrenia is the most neuroleptic-sensitive
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Biochemical Changes associated with Schizophrenia
• Normal or decreased dopamine metabolite in CSF• Increased striatal D2 receptors• Altered expression of D3 and D4 mRNA in specific
cortical regions• Decreased cortical glutamate• Increased cortical glutamate receptors• Decreased glutamate uptake sites in cingulate cortex• Decreased GAD mRNA in prefrontal cortex CG• Increased GABAA binding sites in cingulate cortex
Byne et al, 1999
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DOPAMINE HYPOTHESIS
• Hypodopaminergic state in cortex may underlie the negative symptoms of schizophrenia, while the hyperdopaminergic state in the subcortical area underlie the positive symptoms.
Davis, et al, 1991
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Six types of Dopamine Receptors
PresyanpticDopaminergicNeuron
Cortical or Mesolimbic target neuron
IP3
D3DAG
D3
PIP2
PKC
D2, D3, D4 GiATP ADP
D1, D5
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Dopaminergic Pathways and site of action of various psychoactive
substances
Tyrosine hydroxylase
DOPA Dopamine
MAO
Deaminated products
receptor
COMT
NMInhibition of reuptake
(cocaine, amphetamine. benztropine
Inhibition of reuptake (cocaine, amphetamine.
benztropine
Increase of synthesis
(L-DOPA)
Increase of synthesis
(L-DOPA)Inhibition of
synthesis (-methyltyrosine
Inhibition of synthesis
(-methyltyrosineStimulation of release of DA at nerve terminals (amphetamine,
tyramide)
Stimulation of release of DA at nerve terminals (amphetamine,
tyramide)
blocking of autoreceptors (antipsychotics, perphenazine, haloperidol)
blocking of autoreceptors (antipsychotics, perphenazine, haloperidol)
Inhibition of breakdown (pargyline)
Inhibition of breakdown (pargyline)
Interference with vesicular storage
(reserpine, tetrabenazine)
Interference with vesicular storage
(reserpine, tetrabenazine)
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Chlorpromazine acting on Dopamine Receptors
CHLORPROMAZINE
DOPAMINE
Adapted from Synder, 1986
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Indirect effects of anti-schizophenia drugs on
dopamine receptors
Adapted from R. Zigmond
POSTSYNAPTIC CELL
DOPAMINERGICNEURON
NEURON USINGNEUROTRANSMITTER A
NEURONUSINGNEURO-TRANSMITTERB
(-)
(-)
(-)
Schizophreniaacts here
Drugs acts here
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Serotonergic Innervation of the Frontal Cortex
2A
GABA
5-HT
G G
2A
(-)
(+)
(-)
(+)
GLUTAMATE
GABA
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Serotonergic Innervation of the Piriform Cortex
GABA
5-HT
2A G
2B(+)
(-)
(+)
GLUTAMATE
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ORIGINAL DOPAMINE HYPOTHESIS
VERSUS
RECENT AND COMPLEX ROLE OF DOPAMINE
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Original Dopamine Hypothesis
• DA metabolite and receptor in post-mortem brain do not support this hypothesis (Davis et al, 1991)
• Some schizophrenic patients do not respond to drugs that block dopamine activity
• Negative symptoms of schizophrenia are refractory to such drugs
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Complexity of Dopamine
• DA interact with many other neurotransmitter system (Davis, et al, 1991)
• DA is differentially regulated in different brain regions – hypodopaminergic in the cortex; hyperdopaminergia in subcortical areas
• Phenomenon of depolarization blockade A9 and A10.
• Concept of hypofrontality
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Is there hyperdopaminergia in schizophrenia?
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Is there hyperdopaminergia in
schizophrenia?• Grace (1991) presented a model
pertinent to dopamine function between the prefrontal cortex and subcortical areas based on 2 events:– Transient or phasic dopamine release
caused by DA firing– Sustained or tonic release requested by
prefrontal cortical areas
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Is there hyperdopaminergia in
schizophrenia?New Model Hypothesis:
• Tonic subcortical release of DA would be reduced by decreased activity of cortical efferents leading to an upregulation of subcortical DA receptors, leading to an exaggerated DA response triggered by phasic DA release.
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NMDA Receptor Hypofunction Hypothesis:
DA inhibit glutamate release
• NMDA activation causes neuronal degeneration
• NMDA antagonists may ameliorate the symptoms of degeneration
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• NAN and NAP are inhibited by DA antagonists and GABA agonists
Olney and Farber, 1995
NMDA Receptor Hypofunction Hypothesis:
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• Olney proposes that NMDA receptors tonically drive GABAergic neurons that inhibit excitatory amino acid neurons.
NMDA Receptor Hypofunction Hypothesis:
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• NMDA receptor (NRH) hypofunction would diminish GABAergic inhibition over excitatory inputs to the cortex
NMDA Receptor Hypofunction Hypothesis:
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The role of the thalamus
• THALAMIC PROJECTIONS -
NMDA Receptor Hypofunction Hypothesis:
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• Javitt et al., 1994 – treated chronic schizophenics with glycine – a potentiator of NMDA-receptor mediated neurotransmission.
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The Concept of BRAIN PLASTICITY
Donald Hebb– In 1949, observed
that our ability to change our brain through new data and then to learn occurs because of changes at the neuronal cell levels.
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The Concept of Long-Term Potentiation
A process by which the size of a neuronal response increases after stimulation. This is probably one of the basis of learning.
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David Hubel and Torsten Wiesel
• Both persons explained how experience in the environment affect brain development – a different perspective of brain plasticity.
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Two important components of brain plasticity
• Critical periods
• Activity-dependent changes
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Surface of the Cerebrum
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The Brain in
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Alfred T. Kamajian
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Olfactory bulbOlfactory tract
Anterior commissure
Septal nuclei
Subcallosal gyrus
Anterior cingulate
Corpus callosum Posterior cingulate
Anterior nucleus
Stria terminalis
Hippocampal formation
Hypothalamus
Mammillary body
Entorhinal cortexPiriform cortex
Amygdala
Ring of limbic cortex
Fornix
Medial View of cerebral hemisphere with major limbic structures
indicated