Neurodevelopment NEW

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NEUROBIOLOGY

INTRODNAGENES5-HTDOPABRAIN12043ATOMAUT3

DOPAMINE

B.L. CONDE, MD, FPPA, FPNA

The Neurodevelopmental

Theory of Psychopathology in

Schizophrenia

The lifetime risk for schizophrenia correlated with genetic relatedness

0% 10% 20% 30% 40% 50% 60%

None (General Population)

First Cousin

Uncle/Aunt

Nephew/Niece

Grandchild

Half sibling

Parent

Sibling

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

NEUROBIOLOGY

DOPAMINE

The MIND &BRAIN DICHOTOMY

NEUROBIOLOGY

DOPAMINE

BIOLOGICAL vsPSYCHOLOGICAL

The Basis of Contemporary Neural Science

All mental processes are biological and any alteration in those processes is organic

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 ?

NEUROBIOLOGY

DOPAMINE

GENES vs

ENVIRONMENT

NEUROBIOLOGY

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.

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

Neurodevelopmental hypothesis of schizophrenia suggests that genetics and/or epigenetic events that occur during critical periods of neuronal

growth may negatively influence brain development

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

Retrospective data provide evidence that women in their 2nd trimester (not

1st or 3rd) of pregnancy have an increased risk of offsprings developing schizophrenia

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

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.

Anatomical Evidence That May Support a

Neuro-Developmental Defect

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)

2. Hippocampusa. Finding of cellular architectural disarray

(Kovelman & Scheibel,

b. Decrease in neuronal volume(Heckers et al,

c. Reduction in pyramidal cell density (Jeste & Lohr,

d. Decreases in neuronal sign in subiculum & CA1 (Arnold et al,

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:

Gliosis

• Is the neural scarring following brain lesions other than those that occur early in neurodevelopment

• Characteristic of neurodegenerative disorder

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

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.

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.

MRI of Ventricular System

Nasrallah HA. 2002.

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.

Compelling evidences come from studies of cytoarchitecture which demonstrated that neurons among schizophrenic brains were

MISPLACED,

MIS-SIZED and

DISORGANIZED.

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.

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.

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

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

Maldevelopment in utero sets the stage for secondary disorganization in

adolescence

The lesions remain dormant until normal brain maturation in

adolescence leads to the use of neuronal circuits that are poorly

developed in children

In humans, myelination in circuitry to or from hippocampus is only complete in

adolescence

Clare HoltmanApril 2000

First Episode Schizophrenia

• Enlargement of ventricular system

• Reduction of total brain size

• Reduction of hippocampal size

• No reduction of temporal lobe or amygdala volumes

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

Canadian study found significantly lower total gray matter volumes in 17 young schizophrenia patients (mean

age 20 years) compared to 16 healthy controls

etiological Factors

Risk factors:Nutrition

Seasonality

Infection or infectious

agents

Obstetric complications

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

NEUROBIOLOGY

DOPAMINE

NATURE VS

NURTURE

A Synthetic Model for the Development of Mental

Illness

CAUSESMULTIPLE INTERACTING FACTORS

GENESGENES

GENE EXPRESSION

VIRUSESVIRUSES

TOXINSTOXINSNUTRITIONNUTRITION

BIRTH INJURYBIRTH INJURY

PERSONALEXPERIENCES

Andreasen, NC: Brave New Brain. P36, 2001

Illness

GENESGENES

GENE EXPRESSION

VIRUSESVIRUSES

TOXINSTOXINSNUTRITIONNUTRITION

BIRTH INJURYBIRTH INJURY

PERSONALEXPERIENCES

Illness

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

Illness

BRAIN STRUCTURE AND FUNCTION

MIND FUNCTIONSe.g., memory, emotion, language, attention, arousal, consciousness

Illness

MIND FUNCTIONS

THE UNIQUE PERSON IN A SPECIFIC SOCIAL WORLDe.g., individual behavior and response in a specific

personal and social environment

IllnessCAUSES

MULTIPLE INTERACTING FACTORS

MIND FUNCTIONS

THE UNIQUE PERSON IN A SPECIFIC SOCIAL WORLD

A SPECIFIC MENTAL ILLNESSe.g., schizophrenia, mood disorders, dementias, anxiety disorders

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

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

The initial step in the development of neuronal tissue is the induction of the neural plate.

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

• 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

• 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

Stages of Development• Neuronal formation

• Neuronal proliferation

• Proliferation of dendrites and spines

• Synaptogenesis

• Myelination

• Pruning

• Apoptosis

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.

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

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

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

G1 S G2 M

The plane of division of

progenitor cells in the

ventricular zone influences their

G1 S G2 M

progenitor cells in the ventricular

zone influences their fate

G1 S G2 M

progenitor cells in the ventricular

zone influences their fate

Neuronal differentiation does not stop when a cell leaves the cell cycle and migrates to its final position.

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.

Rita Levi-Montalcini observed that death of neurons is a normal occurrence during embryonic development.

TARGET CELL OF NEUROTROPHIC FACTOR

NEUROTROPHIC FACTOR HYPOTHESIS

Stages of Development

• Neuronal formation

• Neuronal proliferation

• Proliferation of dendrites and spines

• Synaptogenesis

• Myelination

• Pruning

• Apoptosis

The two most plausible developmental processes which may help explain the subplate marker disturbances are defects in either neuronal migration or programmed cell death

Deprivation of neurotrophic factors activates a cell death program in neurons

TARGET CELL OF NEUROTROPHIC FACTORTARGET CELL OF NEUROTROPHIC FACTOR

NEUROTROPHIC FACTOR HYPOTHESIS

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

Guidance of Axons to their Targets

Roger Sperry, a student of Weiss, forwarded the CHEMOSPECIFICITY HYPOTHESIS

The cellular environment provides a complex set of commands to the growing

Axons of retinal ganglion cells follow a complex path to the optic

tectum

TARGET ZONE

TECTUM

The Guidance of Axons to their Targets

Axons from the retina terminate and arborize to their termination site in the tectum

AXONAL ENTRY

AXONAL EXTENSION

AXONAL CORRECTION

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

Elongating axons terminate in a protuberance called the GROWTH CONE.

++++++

+++ ++ ++

+++ ++ ++++ +

++++ ++

--- - -- -

----------

------

---- - -

Extracellular Matrix Adhesion

++++++

+++ ++ ++

+++ ++ ++++ +

++++ ++

--- - -- -

----------

------

---- - -

Cell Surface Adhesion

++++++

+++ ++ ++

+++ ++ ++++ +

++++ ++

--- - -- -

----------

------

---- - -

Pioneer Neuron

Fasciculation

++++++

+++ ++ ++

+++ ++ ++++ +

++++ +

--- - -- -

----------

------

---- - -

++++++

+++ ++ ++

+++ ++ ++++ +

++++ +

Chemoattraction

++++++

+++ ++ ++

+++ ++ ++++ +

++++ +

--- - -- -

----------

------

---- - -

Contact Inhibition

-++++++

+++ ++ ++

+++ ++ ++++ +

++++ +

--- - -- -

----------

------

---- - -

--- - -- -

----------

------

---- - -

Chemorepulsion

Compelling evidences come from studies of cytoarchitecture which demonstrated that neurons among schizophrenic brains were

MISPLACED,

MIS-SIZED and

DISORGANIZED.

Functional Hypothesis for Schizophrenia

Etiology

Hyperdopaminergic state in subcortical area may underlie the positive symptoms of schizophrenia -

Davis, et al, 1991Davis, et al, 1991

DOPAMINE HYPOTHESIS

Neuroanatomical Model of Schizophrenia: Prefrontal Inhibition

PREFRONTAL CORTEX

LIMBIC AREAS

SCHIZOPHRENIA

PREFRONTAL CORTEX

LIMBIC AREAS

NORMAL STATE

Brainstem Dopaminergic neurons

Adapted from Weinberger, 1987

Hypodopaminergic state

in cortex may underlie

the negative symptoms of schizophrenia -

Davis, et al, 1991Davis, et al, 1991

DOPAMINE HYPOTHESIS

The Four Major Dopaminergic Tracts in the Brain

MESOCORTICAL SYSTEM? Involved in the NEGATIVE symptoms ofSchizophrenia

MESOLIMBIC SYSTEM? Involved in the POSITIVE symptoms ofSchizophrenia

Functional Neuroanatomy of Hallucinations in

Schizophrenia

INFERO-TEMORALCORTEX

VENTRAL ANTERIORMAGNOCELLULARDIVISION OF THETHALAMUS

SUBSTANTIANIGRA

PUTAMEN

Dopaminergic Model of Psychosis

• Psychostimulant psychosis results with increasing doses of amphetamines over prolonged use.

Ellinwood, 1967; Post, 1980

• Psychostimulant psychosis results with increasing doses of amphetamines over prolonged use.

• Initial effects are1. Euphoria

2. Enhanced attention

3. Psychomotor agitation

• On repeated exposure, there are1. Perceptual changes

2. Suspiciousness

3. Repetitive behavior

• Chronic use leads to:1. Dysphoria

2. Paranoid delusions

3. Increased distractability

4. Ideas of reference

5. Auditory, visual, tactile hallucinations

The key characteristic of psychostimulant psychosis is sensitization, inducing cross-

sensitization with other drugs or environmental stressor.

• 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.

• Evidences:

• Post-WW II abuse of methamphetamines

• Lieberman et al, in 1987, noted that psychostimulant-naïve schizophrenics become worse when taking psychostimulants.

Sensitization is a function of regulatory abnormalities within the cortico-striato-thalamic circuitry.

Carlsson & Carlsson, 1990, Kalivas, 1995

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

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

• LSD demonstrated partial agonist effect on 5-HT2A receptors

• Mark and Aghajanian, 1996

• 5-HT2A receptors, which mediate hallucinogenic effects play modulatory roles within local cortical circuits.

The Role of Glutamate

• Glutamate communicates with two receptors: AMPA and NMDA

• LTP is enhanced by glutamate activation of NMDA receptors.

Glutaminergic Model of Psychosis

• Luby in 1959 proposed the “phencyclidine model” of psychosis

• Effects of PCP and ketamine are amply similar to schizophrenia

• Rosembaum et al, in 1959, Cohen et al, 1962 compared LSD and PCP cognitive effects in healthy subjects compared to schizophrenics.

Phenomenology of the Model Psychoses

Adapted from Andreasen, 1995

Signs/ Symptoms

5-HT Hallucinogens

Psycho-stimulants

AntagonistsPsychotic Symptoms

Delusions

Hallucinations

Others

++Negative Symptoms

Blunted affect

Withdrawal

Anhedonia

Phenomenology of the Model Psychoses

Adapted from Andreasen, 1995

Signs/ Symptoms

5-HT Hallucinogens

Psycho-stimulants

Antagonists

Disorganization

Thought d/o

Abstraction

Attention

Reduced PPI

+Others (impaired)

Working memory

Declarative memory

Eye movement

Executive functions

• Amphetamine-produced paranoia psychosis are associated with relative sparing of cognitive and thought disorder

• 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.

• Paranoid schizophrenia is the most neuroleptic-sensitive

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

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

Six types of Dopamine Receptors

PresyanpticDopaminergicNeuron

Cortical or Mesolimbic target neuron

D2, D3, D4 GiATP ADP

D1, D5

Dopaminergic Pathways and site of action of various psychoactive

substances

Tyrosine hydroxylase

DOPA Dopamine

Deaminated products

receptor

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)

Inhibition of breakdown (pargyline)

Interference with vesicular storage

(reserpine, tetrabenazine)

Interference with vesicular storage

(reserpine, tetrabenazine)

Chlorpromazine acting on Dopamine Receptors

CHLORPROMAZINE

DOPAMINE

Adapted from Synder, 1986

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

Serotonergic Innervation of the Frontal Cortex

GLUTAMATE

Serotonergic Innervation of the Piriform Cortex

GLUTAMATE

ORIGINAL DOPAMINE HYPOTHESIS

VERSUS

RECENT AND COMPLEX ROLE OF DOPAMINE

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

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

Is there hyperdopaminergia in schizophrenia?

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

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.

NMDA Receptor Hypofunction Hypothesis:

DA inhibit glutamate release

• NMDA activation causes neuronal degeneration

• NMDA antagonists may ameliorate the symptoms of degeneration

• NAN and NAP are inhibited by DA antagonists and GABA agonists

Olney and Farber, 1995

• Olney proposes that NMDA receptors tonically drive GABAergic neurons that inhibit excitatory amino acid neurons.

• NMDA receptor (NRH) hypofunction would diminish GABAergic inhibition over excitatory inputs to the cortex

The role of the thalamus

• THALAMIC PROJECTIONS -

• Javitt et al., 1994 – treated chronic schizophenics with glycine – a potentiator of NMDA-receptor mediated neurotransmission.

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.

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.

David Hubel and Torsten Wiesel

• Both persons explained how experience in the environment affect brain development – a different perspective of brain plasticity.

Two important components of brain plasticity

• Critical periods

• Activity-dependent changes

Surface of the Cerebrum

The Brain in

Alfred T. Kamajian

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

Neurodevelopment NEW

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