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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 • 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 – – – – 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 • 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: – – – – – 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 – – – – – – 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.