Imaging and Nervous System Development

• Medical imaging

• How the nervous system develops

• How the development can malfunction

Imaging Techniques

• 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*– X-rays– CT scans– PET– SPECT

• Structural Imaging– X-Rays, CT, MRI,

(ultrasound)

• Non-ionizing Radiation– MRI– fMRI– (Ultrasound)

• Functional Imaging– 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– 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

• 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

– 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

• Encephalo-meningocele– 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:

– Autistic Disorder– Asperger’s Disorder– Rett’s Disorder– Childhood Disintegrative Disorder– PDD, NOS

• SX Triad: social & language impairments, stereotypical movements.

• Related changes in the medial temporal, orbital frontal lobes, & prefrontal cortex.

Social Language

Compulsions

Pervasive Developmental Disorders

• Autistic Disorder– 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.