Week 1 - Neuro Big Ideas Flashcards
insults to developing embryonic nervous system
first 2 weeks = death, week 3-6 = neural tube defects, >6 weeks = mental retardation
neurulation
from middle in both directions, notochord induces thick neural plate, neural groove becomes neural tube from lateral plate cells, neural crest cell migrate, takes ~ 22 days, somites develop concurrently, derived from ectoderm
neurulation
neural plate –> neural folds –> neural groove –> neural tube and crest cells
neural tube
becomes brain and spinal cord
neural crest cells
becomes PNS, non-neuronal derivations like melanocytes and GI cells
neural canal
ventricular system in brain and canal in spinal cord
neuroepithelial cells
differentiate into neurons with cells bodies in CNS and macroglial cells, ventricular zone = neurons and ependymal cells, intermediate zone = gray matter, marginal zone = white matter
alar plate
becomes dorsal spinal cord, contains secondary sensory neurons, gives rise to afferent fibers
basal plate
becomes ventral spinal cord, contains motor neurons, nerve cell body grows neurites, axons in ventral horn synapse with skeletal muscle, neurons in lateral horn synapse with peripheral autonomic ganglia, gives rise to efferent fibers
roof and floor plates in neural tube
dorsal and ventral thin area with no neuroblasts, become regions of brain where axons cross
primary sensory neuron development
start as bipolar cells and become psuedounipolar
developing brain myelination
schwann cells in PNS, oligodendrocytes in CNS, from neural crest cells, continues throughout first year of life, schwann cell body wraps, oligodendrocyte extensions wrap
length of spinal cord
nerve roots lines up with matching vertebra at 8 wks, vertebra grow faster than spinal cord, newborn spinal cord ends at L2-3, adults spinal cord ends at L1-2, spinal tap below this level
neural tube closure
end 3rd week, creates primary vesicles of brain
primary vesicles of developing brain
forebrain (prosencephalon), midbrain (mesencephalon), hindbrain (rhombenceohalon)
forebrain vesicle (prosencephalon)
becomes telencephalon and diencephalon
midbrain vesicle (mesencephalon)
becomes mesencephalon
hindbrain vesicle (rhombencephalon)
becomes metencephalon and myelencephalon
caudal neural tube
becomes spinal cord
secondary vesicles of developing brain
telencephalon, diencephalon, mesencephalon, metencephalon, myelencephalon
telencephalon vesicle
becomes cerebral cortex, corpus striatum, olfactory bulbs, c shaped growth covers insula, convolutions develop, lateral ventricles, CN I
diencephalon vesicle
becomes thalamus, hypothalamus, epithalamus, subthalamus, third ventricle, CN II
mesencephalon vesicle
becomes tectum, tegmentum, basis pedunculi, superior and inferior colliculus, CN III, CN IV
metencephalon vesicle
becomes pons and cerebellum and fourth ventricle, CN V to XII
myelencephalon vesicle
becomes medulla and fourth ventricle, CN V to XII
cervical flexure
superior bend in secondary vesicles at base of myelencephalon
pontine flexure
inferior bend in secondary vesicles at metencephalon
cephalic flexure
superior bend in secondary vesicle at mesencephalon
choroid plexus
formed by modified ependyma, pia, and blood vessels, floor of fourth ventricles, roof of thrid and fourth ventricles, makes CSF
neural crest cell derivatives
dorsal root ganglia, sympathetic trunk ganglia, celiac ganglia, GI plexis, renal ganglia, suprarenal gland, melanocytes, odontoblasts, bones and cartilage of face
consciousness
wakeful (open eyes, motor arousal) and aware (thoughts, memories, emotions)
coma
unresponsive to internal and external stimuli, no reflexes, unarousable, no eye opening
vegetative state
unresponsive wakefulness, sleep cycles, opens eyes, not aware of others, reflexes, smile/grimace, unresponsive to stimuli
minimally conscious state
sleep cycles, incomplete awareness, + = high level, - = low level
locked in syndrome
sleep cycles, aware, quadriplegia, unable to interact, brainstem lesion
neurological exam
H & P key, changes based on setting
mental status
assessing cortex, level of consciousness, speech, orientation (time and place), attention, calculation (world or months backwards, serial 7s), language, memory (naming, 3 words)
fundoscopic exam
blurring of disk, loss of venous pulse, color
parts of neurologic exam
mental status, cranial nerves, motor, sensory, reflexes, coordination, gait / station
mental status - level of consciousness
determine by observation
mental status - speech
determine by observation
mental status - orientation
determine with person / place / time, month / day / date, city / state / country
mental status - attention / calculation
world backwards, months of year backwards, serial 7s
mental status - language / memory
naming, 3 words (immediate, after distraction)
fundoscopic exam
look for - blurred optic disc, loss of venous pulse, color of optic nerve
testing CN I - olfactory
pass order, perceive not identify
testing CN II - optic (acuity, fields, pupils)
chart, confrontation, eye individually
testing CN III - occulomotor (pupils, eye movement)
direct, consensual, flashlight, conjugate gaze, nyastigma
CN of eye movement
CN III - occulomotor (MR, SR, IR, IO), CN IV - trochlear (SO), CN VI abducens (LR)
testinng CN V - trigeminal (facial sensation, corneal response, mastication)
cotton, pin, tuning fork, compare sides, bite down / open
testing CN VII - facial (facial muscle movements)
observe (palpebral fissures and nasolabial folds), squeeze eyes shut, smile, puff out cheeks, forehead spared = CNS lesion, forehead not spared = PNS lesion
testing CN VIII - vestibulocochlear (hearing, balance)
vestibulo - dizziness, cochlear - finger running, Weber, Rinne
Weber test
on forehead midline,conductive loss louder in affected ear, sensorineural loss louder in unaffected ear
Rinne test
mastoid, in air next to ear, air louder then bone
testing CN IX - glossopharyngeal
palate elevation, gag (coma), swallow, horseness / breathiness
testing CN X - vagus
palate elevation, gag (coma), swallow, horseness / breathiness
testing CN XI - accessory (sternoclidomastoid, trapezius)
turn head against resistance (tests opposite side), shoulder shrug
testing CN XII - hypoglossal (tongue)
listen for slurring, observe protrusion / deviation / slowness (will deviate to weak side)
testing motor
bulk (atrophy, diffuse = disuse, focal = denervated), tone (passive, decreased = flaccid, increased = spastic / rigid / paratonia), strength (grading 5-0, compare sides, compare proximal and distal, arm drift = upper motor neurons)
testing sensory
pain and temp (pin, tuning fork - spinothalamic tract), vibration and propioception (tuning fork - dorsal columns), light touch (cotton - both spinothalamic and dorsal columns)
Romberg test
sensory problems, close eyes and keep balance, positive = neuropathy in feet
testing reflexes
biceps - C5/6, brachioradialis - C6-7, triceps - C7/8, knees - L3/4, ankles - S1/2, Babinski, graded 4-0
clonus
upper motor neuron problem, hyperreflexive, flexed ankle shakes
hyporeflexive
radiculopathy (nerve root problem), neuropathy (sensory nerve problem), PNS
hyperreflexive
brain lesion, spinal cord lesion, upper motor neuron problem, CNS
testing coordination
finger - nose - finger and heel - knee - shin (cerebellum), rapid (frontal), fine finger and toe tapping (upper motor neurons)
testing gait and station
walk - regular, heels, toes, tandem gait
wide, ataxia gait
cerebellum
wide, slapping gait
neuropathy
shuffling, stooped, multistep gait
basal ganglia, parkinsons
spastic gait
upper motor neuron
case - sensory and motor PNS problem, large fibers
dorsal columns, trouble sensing vibration, poor balance, bowel/bladder ok, foot slap, slight motor weakness, positive Romberg, no reflex on area
case - left brain, motor pathways, language, likely left middle cerebral artery lesion in frontal / temporal area
right side of body affected, weakness, sudden, Hx hypertension, trouble speaking, right face weakness sparing forehead, decreased tone, slow finger tapping
case - right side nerve root (C6)
neck / arm pain, weak arm, thumb and 1st finger affected, weak arm flexion, poor sensory in thumb, right biceps weaker then left
brain disorders from most to least common
sleep, hearing, depressive, TBI, stroke, Alzheimer’s. schizophrenia, Parkinson’s, MS, spinal injury, Huntington’s
neurovascular unit
coupled cerebral blood flow and cerebral metabolism, vasodilation in area that is most active, composed of neurons / synpases / astrocytes / capillaries
brain fuel consumption
brain is 2% body weight, uses 25% of glucose and 20% of oxygen in body
neuronal ATP consumption breakdown
44% synpatic transmission (including Ca2+ movement and nt recycling), 25% housekeeping (protein synthesis), 15% resting potential, 16% action potential
fates of glucose in the brain
glycolysis and TCA cycle, 6-10% glycogen synthesis in astrocytes, 3-5% pentose phosphate shunt (makes NADPH for protein synthesis - more in babies)
hexokinase
regulates glucose to glucose 6 phosphate step of glycolysis, inhibited by glucose 6 phosphate, uses ATP
phosphofructokinase
regulates step from fructose 6 phosphate to fructose 1, 6 phosphate in glycolysis, activated by ADP / AMP / Pi, inhibited by ATP / PCr / citrate, uses ATP
pyruvate kinase
regulates the phosphoenolpyruvate to pyruvate step of glycolysis, inhibited by ATP / acetyl-CoA, makes ATP
phosphorylase
turns glycogen into glucose 1 phosphate so it can enter glycolysis, inhibited by cAMP
pyruvate dehydrogenase
turns pyruvate into acteyl-CoA to enter TCA cycle, inhibited by ATP / NADH
isocytrate dehydrogenase
regulates isocitrate to alpha ketoglutarate step of TCA cycle, activated by ADP
alpha ketoglutarate dehydrogenase
regulates alpha ketoglutarate to succinyl-CoA step of TCA cyce, inhibited by ATP
cerebral metabolic rate - glucose (CMR-G)
positive number because brain is consuming glucose, (A-V)F/W
cerebral metabolic rate - oxygen (CMR-O)
positive number because brain is consuming glucose, (A-V)F/W
cerebral metabolic rate - lactate
negative number because brain is producing lactate, (A-V)F/W
cerebral metabolic rate - CO2
negative number because brain is producing CO2, (A-V)F/W
cerebral metabolic rate - XXX equation
(A-V)F/W, A - arterial conc in mole/l, V venous conc in mol/l, F = blood flow in l/min, W = weight in grams, CMR unit = moles/g/min
CMR-O2 vs CMR-G ratio
5:1, 156 to 31, 6 O per glucose to make ATP, some glucose not being oxidized and becoming lactate - that is why it is not a perfect 6:1 ratio (1 glucose + 6O2 –> 6CO2 + 6 H2O
CMR-O2 and CMR-CO2 ratio
1:1
drowning CMR-G and CMR-O
CMR-G up because making energy with glycolysis, CMR-O down because none available
anesthetic CMR-G and CMR-O
depressants / less brain activity = less energy needed, CMR-G and CMR-O down
epilepsy CMR-G and CMR-O
seizures = more energy needed, CMR-G and CMR-O up
2-deoxyglucose (2-DG)
glucose analogue, glucose transporter into cells, phosphorylated by hexokinase to glucose 6 phosphate, then gets stuck in glycolysis pathway, use to locate areas of high glucose metabolism by marking it with radioactive fluroine-18 (often used in PET scans)
PET scan of Alzheimer’s brain
low metabolic activity in parietal / temporal / occipital lobes
PET scan of frontal temporal dementia
shows decreased metabolism in frontal / temporal lobes
effect of visual stimulation on brain
increased blood flow / glucose / O2 to occipital area, but not increase O2 usage because brains uses aerobic respiration to meet the needs of momentary visual stimulation
aerobic glycolysis
glycolysis in the presence of O2, when excess pyruvate is made it is shunted to lactate
astrocyte-neuron lactate shuttle
astrocytes take up 80% of the glucose in brain and shuttle it to neurons, glutamate and Na+ through GLAST / GLT1 triggers alpha subunit of Na/K - ATPase –> glucose uptake through GLUT1 –> glycolysis to lactate with LDH5 –> release of lactate via MCT1 / 4 –> reuptake of lactate in neuron by MCT2 –> LDH1 converts lactate back to pyruvate –> TCA cycle
glutamate / glutamine shuttle
glutamate and Na+ are cotransported from neuron to astrocyte, Na+ influx triggered Na/K ATPase in astrocyte, glycolysis occurs making lactate to meet ATP needs of ATPase and glutamate to glutamine conversion, glutamine trasported to neuron via GLAST/GLT1 and used as glutamate neurotransmitter, lactate transported to neuron via MCT1/4/2 and turned back into pyruvate by LDH1 then enters TCA cycle
acetoacetate and D-3-hydroxybutyrate
ketone bodies, three conditions when the brain can use for TCA cycle –> suckling newborn, fasting adult, ketogenic diet adult, hibernation, product of fatty acid break down in the liver mitochondrion
ketones + antioxidants + hypothermia
common therapy for blood loss, stroke, and cardiac arrest, because it requires 28% less O2 to sustain the brain with ATP
case - 4 month old baby, odd eye movements, limb jerking, CSF glucose low (should be 2/3 of plasma glucose), head circumference low
mutated glucose transporter in endothelial cells prevents glucose from entering and brain can’t grow, normal diet causes seizures, need to be on ketogenic diet
blood brain barrier
dye put into veins shows up in all body tissues but brain tissue, dense capillary network, endothelial cells joined by tight junctions, tight junctions promoted by pericytes, astrocyte end feet on capillaries, anything that gets into the brain must go through endothelial cells by crossing the luminal and abluminal membranes and diffusing through the cytoplasm
tight junction
form blood brain barrier, transmembrane proteins with extracellular loops made of claudin and occludin and junctional adhesion molecules (JAM)
paracellular aqueous pathway
not a usual pathway into the brain by water soluble agents due to blood brain barrier, through tight junction
transcellular lipophilic pathway
rare pathway into the brain across enodothelial membrane by lipid soluble agents, ex: steroids, alcohol, and drugs of abuse
transport protein pathway
common way into the brain, transport proteins move glucose, amino acids, and nucleosides
monocarboxylate transporter 1 (MCT1)
12 transmembrane segments, moves lactate and H+, pyruvate, acetate, and butyrate during times of exercise and hypoglycemia; moves ketones during times of fasting and ketogenic diets; in membrane of endothelial cells, number of transporters changes based on conditions ex: more in suckling infants and in ketogenic diet adults
GLUT1
transports glucose via endothelial cells into / out of brain
MCT1
transports lactic acid and ketone bodies via endothelial cells into / out of brain
LAT1
transports amino acids vie endothelial cells into / out of brain
ENT1, CNT2
transports adenosine via endothelial cells into / out of brain
FATP1
transports fatty acid via endothelial cells into / out of brain
CT1
transports creatine via endothelial cells into / out of brain
aquaporins
transport H2O in / out of brain across the epithelium in the choroid plexus
p-glycoprotein, Mdr1, Bcrp1
12 transmembrane segments, only in lumenal membrane of endothelial cells, efflux transporter, substrate non-specific, pumps xenobiotics back into blood making it hard to treat the brain directly with drugs, ex: erlotinib a tyrosine kinase inhibitor for cancer can enter the brain better in mice that have had efflux transporters knocked out
diseases affected by the blood-brain barrier
MS, Alzheimer’s, epilipsy, creatine transporter defect, pathogenic infections - when an endothelial cell is dysfunctional all the ones around it are too resulting in neurological disease
transcytosis
receptor on lumenal surface binds things like insulin and transferin allowing them to be endocytosed into the brain
LRP receptor
peptide binding protein, allows agent endocytosis into brain across endothelium, drugs linked to a peptide will also be endocytosed, called trojan horse approach
immune cell migration
immune cells can get into the brain by passing through endothelial cells, called diapedesis, happens in response to chemokines that are released by MS (is an autoimmune disease), stroke, TBI - could be used as a form of brain immunotherapy to target cancer cells
formation of blood brain barrier
forms in first few weeks of embryonic development, neuropil expresses Wnt which causes endothelial cells to migrate into neuropil and establish vasculature
blood-CSF barrier in choroid plexus
blood vessels in choroid plexus are leaky and the epithelial cells tight junctions, has aquaporins, Na+ and H+ inverse transporter, and bicarbonate and Cl- reverse transporter are all on the ECF side of the choroid plexus, Na+ / K+ / and 2 Cl- ATPases on CSF side move ions into CSF, aquaporins move H2O into CSF, ions and bicarbonate make CSF high osmolarity so water follows, bicarbonate is also made by carbonic anhydrase in epithelial cell, there are also nutrient transporters but not as key as in blood-brain barrier
neurons
transmit impulses
astrocytes
CNS - react to injury, create blood brain barrier, many cellular extensions, large spotted nucleus
oligodendrocytes
CNS - produce myelin, dark small nucleus
microglia
CNS - phagocytize intruders, elongated squished nucleus
ependymal cells
CNS - line ventricles in single layer, have cilia
acute injury
neuron reaction to injury, red = dead, often from lack of blood flow, cells not as plump
subacute / chronic injury
neuron reaction to injury, like degeneration - neurons seem to disappear
axonal reaction
neuron reaction to injury, axonal spheroids from swelling, trying to make proteins to fix things
inclusions
neuron reaction to injury, can be viral or degenerative, Cowdry A, Negri,
Cowdry A inclusion
red center, white halo, basophilic ring, viruses in cell, herpes
Negri body
eosinophilic circle in cell body with sharp edges, seen with rabies
neurofibrillary tangles
Alzheimer’s cell dying, dark lines
Lewy body
pink circle, fuzzy edges, Parkinson’s
gliosis
accumulation of astrocytes after injury, “scar” in CNS, astrocytes are numerous and bigger
gemistocytic astrocytes
astrocytes that look big, plump, pink - reacting
rosenthal fibers
long eosinophilic astrocyte processes where there has been longterm gliosis
corpora amylacea
degenerative change, aging, carbohydrates in round purple cells
microglia
proliferate, long nuclei, form nodules around dead cells, necrosis, bacteria, infection, and injury
nerve reaction to axon transection
distal nerve function lost –> resealing of cut axons (hours), retrograde and anteretrograde transport stops
retrograde transport in cut axon
transport up axon to cell body stops
anteretrograde transport in cut axon
distal stump Wallerian degeneration, rapid fragmentation after 2-3 day latent phase, myelin disintegrates, macrophages and Schwann cells removel remnants in PNS only, neuron chromatolysis, target cell atrophy
PNS axon regeneration
Schwann cells redifferentiate, proliferate, and release factors that stimulate axon regrowth and recruit macrophages, increased expression of growth related genes in neurons like GAP43, axon cuts in PNS prime CNS for repairing axon cuts, connective tissue forms supportive bridge (more with crush, less with cut), lack of axonal growth inhibitors that are present in CNS, strength and sensation a little reduced because axons don’t hit target perfectly - can form traumatic neuroma, 2-4mm/day with crush
CNS axon regeneration
more limited, aborted after 1 month, myelin produces inhibitors of axon growth (nogoA and myelin associated glycoprotein MAG), oligodendrocytes don’t clean up myelin and macrophages are hard to recruit, astrocyte proliferation forms glial scar that produces inhibitory chondroitin sulfate proteoglycan CSPG, CNS neurons have receptors for inhibtors and change gene expression not favoring plasticity
CNS plasticity in adults
neurogenesis in two regions - hippocampus and olfactory nerves
strategies to promote axonal regeneration in CNS
neutralize myelin inhibitors (nogoA and MAG), enzyme chondoitinase degrades CSPG from glial scar, enhance growth signaling pathway by increasing cAMP
strategies to promote cell replacement in CNS
growth factors to recruit progenitor cells, transplant embryonic stem cells or induced pluripotent stem cells, transplant supportive cells like oligodendrocytes
strategies to promote CNS plasticity
remaining axons can sprout new connections or increase synaptic strength, Tx to increase plasticity = chondroitinase to inhibit CSPG and physical therapy
critical period in brain plasticity
up to 5 years old, ends with maturation of inhibitory neurons like GABA neurons and effects of CSPG
two sources of skull embryologically
- paraxial mesoderm –> occipital somites –> base of skull, 2. neuroectoderm –> neural crest –> mesenchyme in pharyngeal arches –> bones of face and skull
somitomeres
somites 1-7, from paraxial mesoderm, contribute to head myotome, neuromere, and sclerotome
embryological head
derived from somitomeres 1-7 and occipital somites 1-4
neurocranium
brain case, forms around rostral end of neural tube, neural tube induced, cartilaginous and membranous ossicifcation
viscerocranium
face, taste / sight / smell organs, forms around gut tube rostral to notochord
cartilaginous (endochondral) ossification in neurocranium
ethmoid, sphenoid, occipital base, petrous temporal, temporal-mastoid; skull base
intramembranous ossification in neurocranium
flat bones - parietal, frontal, squamous occipital; occurs in a radial pattern
bones of skull from neural crest (pharyngeal arch) mesenchyme
frontal, squa. temporal, sphenoid, bones of face, hyoid
bones of skull from paraxial mesoderm (somites / somitomeres) mesenchyme
pet. temporal, occipital, parietal
bones of skull from lateral plate mesoderm mesenchyme
laryngeals
cartilaginous (endochondral) ossification in viscerocranium
malleus, incus, stapes, hyoid, styloid, temporal
membranous ossification of bones in viscerocranium
premaxilla, maxilla, zygomatic, squamous temporal, mandible; form from mesenchyme in pharyngeal arches
pharyngeal arches
mesenchymal cells migrate from neural crest
newborn skull
1/4 of body length, becomes less with age
newborn skull sutures
frontal / metopic, coronal, sagittal, lambdoid - dense connective tissue
newborn skull fontanelles
anterior (becomes bregma), posterior (becomes lambda), posterolateral / mastoid, anterolateral / sphenoidal
skull molding
overlapping of skull bones at sutures during birth, returns to normal in 24 hours
frontal / metopic suture
begins closing at 2 years, done closing by 8 years
changes to developing skull after birth
brain and cranial vault growth (midline moves from brow to center of eyes), growth of sinuses, eruption of teeth, growth of mandible
CT without contrast
good for blood and bone imaging of head, sensitive to fine fractures (over x-ray),contrast turns things white and blood looks white = bad
MRI
good for imaging brain itself, tumors, abcesses, etc.
imaging contrast
avoid using in pt with renal failure and in pt with possible brain bleed (can’t see blood)
retrograde
traveling up an axon toward neuronal cell body
anteretrograde
traveling from neuronal cell body to axon terminal
