Transcript Lecture 2 Imaging, Brain Development

Imaging and
Nervous System Development
• Medical imaging
• How the nervous system develops
• How the development can malfunction
Imaging Techniques
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Key tool in modern research
Non- or minimally-invasive/harmful
Mostly based on some sort of radiation
Can be anatomical or functional
Ionizing Radiation
Non-invasive Medical Imaging
• Ionizing Radiation*
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X-rays
CT scans
PET
SPECT
• Non-ionizing Radiation
– MRI
– fMRI
– (Ultrasound)
• Structural Imaging
• Functional Imaging
– X-Rays, CT, MRI,
(ultrasound)
– fMRI, PET, SPECT
* Ionizing radiation can change genes or kill cells
X-Rays
• The 1st (1895) medical imaging modality.
• Good for structural (bone) imaging.
• Disadvantages:
– Not great at differentiating soft tissues.
– X-radiation is ionizing (dangerous).
– Images are projections
• Many layers are blurred together and cannot be
separated.
• Image is distorted so accurate measurement cannot
be taken.
• Not commonly used for brain imaging.
1st X-ray 1895
X-Rays
• Areas of high absorption
(bone) show up as white
in the final X-ray image.
• Areas of medium
absorption (tissue) show
up as gray.
• Areas of low absorption
(air) show up as black.
Computed Tomography (CT)
• Invented in 1972 by Sir Godfrey Hounsfield
• Uses X-rays, so ionizing radiation is a still a
problem
• Also primarily for structural imaging
• Two main advantages over X-rays:
– CT images are not projections, so each organ,
bone and tissue is clearly separated, and
measurements are accurate.
– The data obtained at each pixel is meaningful.
CT
• A number of X-rays
are taken from
different angles and
combined into one
computed image by a
massive regression
analysis. Combined,
they form a 3-D
representation of the
patient.
CT
Magnetic Resonance Imaging
(MRI)
• fka Nuclear Magnetic Resonance (NMR)
• MRI is much better than CT at
differentiating tissue types, so it is better for
soft-tissue structural imaging.
• There are no known harmful effects at
reasonable magnetic fields.
• MRI studies are more expensive than CT
studies.
MRI
• Typical MRI:
– A large supercooled
magnet
– Radio emission coils
(in the tube)
– Radio detection coils (a
head coil is shown)
MRI
• Acoustic schwannoma
– Dr. P’s neoplasm of cranial
nerve 8 myelin sheath
Midline brain view
Positron Emission Tomography
(PET)
• Functional imaging – What areas are working?
• The brain is fueled by glucose (sugar). Inject a
radioactive form of sugar, and see where it is
used the most.
• Inject patient with radiopharmaceutical, usually
2-deoxyglucose (2-DG) or FDG.
• Give the subject a task, and allow some time for
it to collect in some place interesting.
Positron Emission Tomography
(PET)
• The positrons from the radiopharmaceutical
annihilate electrons and send 2 photons in
opposite directions.
• Take a picture of the patient, only counting
photons which have counterparts 180 degrees
away.
• The radioactive pharmaceuticals have very short
(1/2 hour) half-lives.
• Advantages:
– Radiation levels are low and short-lived, therefore
relatively harmless to patient.
Positron Emission Tomography
(PET)
• Disadvantages:
– Short half-life means hospital must have an
accelerator on-site (very expensive).
– A long exposure is required (40 sec) because of
low radiation levels.
– Low spatial resolution (4 mm) due to
annihilation distance.
– Images are projections, no anatomical
measurements are possible.
PET
• Language
areas by
PET
SPECT
• Functional imaging
• Single Photon Emission Computed Tomography
• The radiopharmaceutical directly emits single 140
KeV gamma photons.
• Half-life of about six hours for Tc-99m
– Can be manufactured inexpensively off-site
• Less versatile and less detailed than PET, but
much less expensive.
Functional MRI (fMRI)
• Produces images of the increase in O2 flow
in the blood to active areas of the brain.
Advantages over PET -• Nothing has to be injected into subject.
• Provides both structural and functional info.
• Spatial and time resolution are better.
fMRI
• Study of
speech area
activation in
bilingual
speakers
DTMRI
• Diffusion Tensor
MRI
– Shows pathways
– Previously only
available by
dissection and
staining
Development of the NS
• DNA holds the master plan
– DNA encodes genes
– Genetic is not the same as hereditary
• There are critical periods for certain steps
• Development is unidirectional
– Ever increasing complexity
– Ever increasing specialization
Development of the NS
• Embryonic phase
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Sperm penetrates and fertilizes an ovum.
The two haploid genomes merge.
The resulting cell can now undergo mitosis.
Straight mitotic division (no specialization)
until about 32 cells (5 generations).
– Specialization starts very early.
Development of the NS
• Embryonic phase
– Differentiation begins shortly after 32 cells.
– Ecto-, Meso-, and Endo-derm differentiation
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ecto- = surface
meso- = middle
endo- = inside
-derm = skin
– Day 15: Formation of a neural streak in the
ectoderm.
Development of the NS
• Embryonic phase
– Day 18: Neural plate
thickens on dorsal surface.
– Day 19-20: Neural groove
forms.
– Day 21: Neural groove joins
at dorsal center.
– Day 22: Neural tube forms,
optic groove.
– Day 25: Neural tube closes.
Development of the NS
• Embryonic phase
– Day 28: Neural tube forms
3 swellings:
• Prosencephalon (forebrain)
• Mesencephalon (midbrain)
• Rhombencephalon
(hindbrain)
– Weeks 3-8: Brain most
sensitive to teratogens.
Development of the NS
• Embryonic phase
– Day 35: Cerebellum
starts forming from
rhombencephalon.
– Weeks 6-18:
Cerebrum starts
forming from
prosencephalon.
Development of the NS
• Embryonic phase
– Week 12: Limbic system structures form,
myelination begins, swallow reflex.
– Week 14: Longitudinal and lateral fissures form.
– Weeks 16-39: Gyri form.
– Week 24: Sucking reflex.
– Week 28: Synaptogenesis starts.
– Myelination begins before birth, but isn’t finished
until about puberty.
Development of the NS
• Infant phase
– Week 39: Birth – cortex is about 2/3 of brain.
– 3 months: Right and left “Broca’s” areas are
developing equally fast. Visual neuron
myelination completes.
– 3-12 months: Right “Broca’s” area grows faster.
Gestures and prosody appear.
– 12-15 months: Left Broca’s area overtakes
right. Speech emerges.
Development of the NS
• Infant phase
– 9-10 months: Motor neuron myelination
completes. Hands start using pincer action,
locomotion emerges. Rapid synaptic density
increase in frontal lobe.
– 2-4 years: Occipital lobe fully developed
– 5-6 years: Lateralization complete. Recovery
prospects are minimal.
– 12-16 years: Frontal lobe fully developed.
Development of the NS
• Piaget’s Development Stages
– Sensorimotor Stage, 0-2 years
• Child changes from a reflexive reactor to an
operator, and develops object permanence.
• Emergence of language
• Myelination of visual, sensory, and motor systems
• Rapid frontal lobe synaptic density increase
– Preoperational Stage, 2-7 years
• Child develops mental representations of objects,
and uses words and/or pictures to express these.
• Maturation of language, lateralization completes
Development of the NS
• Piaget’s Development Stages
– Concrete Operational Stage, 7-11 years
• Child develops logical thinking
• Continued development of frontal lobe
– Formal Operational Stage, 11+ years
• Child develops abstract thinking
• Frontal lobe is close to being mature
Cortical Development
• Cortex develops from the inside out.
• Neural precursors divide near ventricles.
• Immature daughter cells migrate to cortex
along radial glia.
• Cells specialize in subplate and migrate to
their final positions.
• Chemo-attractors and –repellants guide
neural migration.
Development Pathologies
• Causes:
– Genetic
• Non-46, microdeletions, mutations, Fragile X
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Environmental: anoxia, malnutrition, trauma
Toxins: drugs, lead, mercury
Infections: rubella, mumps, flu, CMV, herpes
Metabolic: PKU
Development Pathologies
• Embryonic phase critical periods
– Dorsal induction phase, 3-4 weeks
• Neural tube closure
– Ventral induction phase, 5-6 weeks
• Major brain segmentation, facial abnormalities
– Proliferation phase, 2-4 months
• Variations in numbers of neurons
– Migration phase, 3-5 months
• Anomalous formation of cortex
– Organization/Differentiation, 6 mo – 3 years
• Synaptic abnormalities
– Myelination, 6 mo. – adulthood
• Neural conduction
Dorsal Induction Pathologies
• Non-closure of neural tube
– Always fatal
Dorsal Induction Pathologies
• Spina Bifida
– “Split spine”
– Incomplete closure of
inferior end of neural tube
– Opening can be
microscopic
– Rarely fatal
Dorsal Induction Pathologies
• Anencephaly
– “No brain”
– Neural tube fails
to close at
superior end
– Almost always
stillborn
Dorsal Induction Pathologies
• Encephalomeningocele
– Pouch in brain
coverings
– Often external
Dorsal Induction Pathologies
• Hydrocephalus
– Abnormally large
ventricles
Ventral Induction Pathologies
• Holoprosencephaly
– Brain does not divide
into two hemispheres
– Possible cyclopia
Proliferation Pathologies
• Microcephaly
– Small head and brain
– Smaller number of neurons
13 year old μ
Normal 11 year old
Migration Pathologies
• Defects at start of neural
migration at 11-13 weeks.
• Agyria or lissencephaly
– No gyri, smooth brain
– SX: severe mental retardation,
microcephaly & seizures
• Pachygyria
– “Elephant gyri”, fewer and
oversized
– SX: spasms, epilepsy,
developmental delays
Migration Pathologies
• Polymicrogyria
– Migrational anomoly at
12-14 weeks.
– Many too small gyri
– Usually starts at 5-6
weeks, often from a
uterine infection.
– SX: MR, CP, seizures
Migration Pathologies
• Heterotopia
– Migrational anomoly at
2-5 months.
– White and gray matter
are homogenous instead
of separated.
– Males usually stillborn.
– Females generally
normal, but with
seizures.
Pervasive Developmental Disorders
• Broad spectrum of disorders:
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Autistic Disorder
Asperger’s Disorder
Rett’s Disorder
Childhood Disintegrative Disorder
PDD, NOS
Compulsions
Social
• SX Triad: social & language impairments,
stereotypical movements.
• Related changes in the medial temporal,
orbital frontal lobes, & prefrontal cortex.
Language
Pervasive Developmental Disorders
• Autistic Disorder
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1:2500, M = 4xF
MZ = 36-96%, DZ = 0-24%
Onset prior to age 3.
1. Social impairment.
2. Impaired verbal and non-verbal communications.
3. Restricted repetitive and stereotyped behaviors,
interests and activities.
– Mild to profound MR.
Pervasive Developmental Disorders
• Autistic Disorder
– Miller & Strömland (1993) found critical period
at 20-24 days, HOXA-1 gene involved.
– Many brain differences including corpus
callosum, frontal lobe, etc.
– Neural migration problems in amygdala and
hippocampus.
– Neonatal blood of autistic children often contains
elevated levels of neural growth factors.
– About 30% have hyperserotonia.
Pervasive Developmental Disorders
• Asperger’s Disorder
– 1:300-400
– 1. Social impairment.
– 2. No significant delay in language
• Early speech and good grammar.
– 3. Restricted repetitive and stereotyped
behaviors, interests and activities.
– Average or above intelligence.
Pervasive Developmental Disorders
• Rett’s Disorder
– 1:10000, females only. Lethal in 46, XY males.
– 80% have mutation of Xq28 MECP2 control gene.
– 1. Normal pre- and peri-natal and psychomotor
development until 5 months. Normal birth head size.
– 2. 5-48 months onset: decelerated head growth, loss
of social engagement, replacement of purposeful
hand movements with stereotyped movements, loss
of coordination.
– 3. Severe language impairments.
– Severe to profound MR.
Pervasive Developmental Disorders
• Childhood Disintegrative Disorder
– 1. Normal language and social development through
at least 2 years of age.
– 2. Loss of previously acquired skills before age 10:
• Language, social, motor, bowel, play
– 3. Develops language impairments, social
impairments, and stereotyped behaviors.
– Severe to profound MR.