week 5 Flashcards
(131 cards)
1
Q
autism incidence
A
23% increase since 2009
4:1 male to female
lower rates in minorities
13% more diagnosed by age 3
2
Q
autism genetics
A
20% have identifiable genetic disorders
60% monozygoitic twin concordance
20% chance of 2nd child having an ASD
recurrent chromosome abnormalities = ~5-10%
3
Q
genetic diseases associated with autism
A
fragile X syndrome 1-2%
tuberous sclerosis <1%
4
Q
brain regions affected in autism
A
amygdala
frontal cortex
striatum
cerebellum =
5
Q
early dysregulation of brain growth
A
unusually rapid rate of early brain growth followed by asymptote between 2-4 years of age. Likely impaires connectivity. Main area affected is frontal lobes
mocephaly 30% = >2 SD above average head circumference
6
Q
connectivity in autism
A
local over connectivity and regional under connectivity
problem of multiple circuits, not one structure
7
Q
developmental disconnection in autism
A
don’t have normal cross talk in brains of autism patients
due to disconnection during development
8
Q
diagnostic criteria for autistic disorder
A
- impairments in social interaction
- impairments in communication
- restricted, repetitive and stereotyped patterns of behavior, interests and activities
- delay or abnormal functioning in at least 1 area before age 3 YO
= social interaction
= language as used in social communication
= symbolic or imaginative play - not better accounted for by Rett’s disorder or childhood disintegrative disorder
9
Q
Asperger’s Disorder
A
- impairments in social interaction
- restricted, repetitive and stereotyped patterns of behavior, interests and activities
- causes clinically significant impairment in functioning
- no significant general delay in language
- no significant cognitive or adaptive delay
10
Q
Pervasive development disorder not otherwise specified (PDD-NOS)
A
impairment in the development of reciprocal social interaction PLUS
- impaired verbal or non-verbal communication skills OR
- stereotype behavior, interests and activities
11
Q
joint attention
A
Shared attention, being able to engage with another person. Examples include following a point or shared enjoyment in an activity.
impaired in ASD
12
Q
social impairment in ASD
A
joint attention
play
object focused
13
Q
expressive language impairment in ASD
A
smaller spontaneous vocabulary
14
Q
repetitive behaviors
A
ASD
15
Q
Comorbidities with ASD
A
sleep disturbance epilepsy = EEG abnormalities motor problems: apraxia GI disturbance macrocephaly = big heads
16
Q
comorbid psychiatric conditions
A
ADHD
social impairment
aggression
OCD
17
Q
sleep impairment in autism
A
80% of patients
INSOMNIA (most common) = delayed sleep onset, night awakening, early morning awakening, reduced need for sleep
18
Q
sleep study EEG abnormalities in ASD
A
longer sleep latency
increased duration of stage 1 sleep
decreased non-REM sleep (stages 2-4)
abnormal REM sleep
19
Q
epilepsy
A
abnormal EEG’s reported in up to 50%
epilepsy reported in ~30% = having >1 unprovoked seizure
no primary seizure type
two peaks = early childhood and adolescence
many genetic disorders associated with both ASD and epilepsy
20
Q
epilepsy features in ASD
A
link to intellectual disability (ASD + ID = more likely to have epilepsy)
link to developmental regression
more common in ASD girls
often have more motor and behavioral impairments
21
Q
motor impairment in ASD
A
repetitive behavior = part of diagnostic criteria
1. insistence on sameness
2. repetitive behaviors (stereotypes)
often become more severe over development
more predominant in children with severe language impairment
22
Q
types of motor impairment
A
motor delay hypotonia: improves over time incoordination gait impairment: toe walking common aprazia motor planning postural control
23
Q
significance of motor impairment in ASD
A
implications for outcomes
link between gesture/imitation and language acquisition
link between motor planning and procedural/pattern based learning
Tx: Risperidone for repetitive behaviors
24
Q
Psychiatric comorbidities
A
Shared attention, being able to engage with another person. Examples include following a point or shared enjoyment in an activity.
25
Early diagnosis/screening for ASD
Early diagnosis --> Early intervention --> Improved outcomes
behavioral differences appear at 12 mo old (less initiating and responding to joint attention, less requesting, more object focused)
26
screening tools @ 18 months standard
M-CHAT (for younger children) - performed at 18 mo wild child check
PDDST-II
Autism Screening Questionnaire
27
Referral to specialist WHEN?? -
Fail screening questionnaire (2 or more high yield questions)
no babbling or pointing by 12 mo
non spontaneous single words by 16 mo
no 2 word spontaneous phrases by 24 mo
ANY loss of language or social skills at any age (esp < 24 mo)
28
M-CHAT high risk questions = FAIL 2 or more = REFERRAL TO SPECIALIST
2. Does your child take an interest in other children?
7. Does your child ever use his/her index finger to point, to indicate interest in something?
9. Does your child ever bring objects over to you (parent) to show you something?
13. Does your child imitate you? (e.g., you make a face-will your child imitate it?)
14. Does your child respond to his/her name when you call?
15. If you point at a toy across the room, does your child look at it?
29
recommended diagnostic workup
additional neuropsychological to test IQ, behavioral or emotional problems, learning profile
30
medical workup for ASD diagnosis
GENETIC TESTING (only recommended test)
karyotype
fragile X
MECP2 mutation testing
chromosomal microarry analysis
MRI = only if abnormal neuro exam or global developmental delay
EEF only if concern for seizures or language regression
31
autism treatment
1. treatment for at LEAST 25 hrs/wk
2. high staff: student ratio (1:2)
3. teachers with special expertise in autism
4. individual programs for each child
32
behavioral treatment for ASD
ABA = applied behavior analysis = shape and reinforce new behaviors with positive reinforcement
PRT pivotal response training = play based (good for younger children)
DIR/Floortime (developmental, individual difference, relationship based) = builds on child's abilities
JASPER = joint attention symbolic play emotion regulation = play based
33
pharmacotherapy for ASD
approved by FDA for children ages 5-16 with ASD for irritability (atypical antipsychotics)
1. risperidone
2. aripripazole (abilify)
no meds shown to change social interaction or communication (i.e.: core deficits)
34
treatment for sleep impairment in ASD
behavioral interventions = bedtime routines, reinforcement & extinction, parent training
pharmacologic = melatonin, clonidine, trazadone
35
epilepsy treatment in ASD
```
anti-epileptics
Leviteracitam: behavioral side effects
Valproic acid: liver toxicity
Benzodiaxepines: dowsiness
Lamotrigine: Steven Johnson syndrome
```
36
plasticity of the brain vs. efficiency
brain sacrifices plasticity for the sake of efficiency
environmental and intrinsic factors influence the timing
temporal and spatial implications for sacrificing plasticity: too early, or too late
37
myelination in the brain
rapidly increases from birth
| and increases with age
38
structural connectivity
increases from birth into childhood
| decreases with age = PRUNING
39
size of brain
brain size changes little after age of 7 yrs but the synaptic connections and white matter change
40
myelination increases until ~40 YO
dramatic increases in myelination occur long after the brain has reached the bulk of its adult volume
41
synaptic density
dramatic changes in synaptic density continue into adolescence
reductions in synaptic density and increased myelination likely underlie maturational changes in cortical structure seen with MRI
42
REDUCTIONS in synaptic density and increases in myelination during childhood & adolescence cause
increased efficiency at the cost of decreased plasticity
plasticity of connections = early over abundance of synapses and lack of insulating myelin allow plasticity in cortico-cortical connections
43
pruning of synaptic connections
during development, less used connections die away and more used circuits are insulated with myelin = increases conduction speed
44
white matter development
increased in adults
peaks ~40 YO
gray matter decreases (thins) with time as white matter expands over time = thinning of the cerebral cortex
45
plasticity of the brain vs. efficiency
brain sacrifices plasticity for the sake of efficiency
environmental and intrinsic factors influence the timing
temporal and spatial implications for sacrificing plasticity: too early, or too late
46
myelination in the brain
rapidly increases from birth
| and increases with age
47
structural connectivity
increases from birth into childhood
| decreases with age = PRUNING
48
size of brain
brain size changes little after age of 7 yrs but the synaptic connections and white matter change
49
myelination increases until ~40 YO
dramatic increases in myelination occur long after the brain has reached the bulk of its adult volume
50
synaptic density
dramatic changes in synaptic density continue into adolescence
reductions in synaptic density and increased myelination likely underlie maturational changes in cortical structure seen with MRI
51
REDUCTIONS in synaptic density and increases in myelination during childhood & adolescence cause
increased efficiency at the cost of decreased plasticity
plasticity of connections = early over abundance of synapses and lack of insulating myelin allow plasticity in cortico-cortical connections
52
pruning of synaptic connections
during development, less used connections die away and more used circuits are insulated with myelin = increases conduction speed
53
white matter development
increased in adults
peaks ~40 YO
gray matter decreases (thins) with time as white matter expands over time = thinning of the cerebral cortex
54
cortical thickness with age and relative to regions
cortex is thicker in frontal regions relative to other areas in younger children
thickness declines occur more rapidly in parietal than frontal regions
55
testosterone mediation of brain development
more testosterone in boys = thicker cortex - suggests delayed development = extended period of plasticity; slower rate of thinning
56
testosterone effects on boys
extended occipital/limbic plasticity in boys - thickening of occipital and limbic cortices
57
testosterone in girls
advanced frontal efficiency in girls - thinning of occipital and limbic cortices
58
changes in brain related to cognitive functioning
ex: thicker cortex related to worse vocabulary
children whose cortex thins more over time improve more on vocab
more rapid cortex thinning in left hemisphere learn morn words over time than children with slow thinning cortex
thinning cortex may result in increased efficiency
59
thinning cortex in children relative to intelligence
superior intellectual functioning = later peaks in cortical thickness followed by pruning and myelination - more dynamic cortex (extend period of plasticity = advantageous for general intellectual functioning)
average children = show peaks and declines in cortical thickness much earlier
60
advantage of delated pruning in children
```
more dynamic cortex
sacrificing plasticity (flexibility) too early (pruning) = reduces amount of time to gain experience to build the most efficient connections before insulating with myelin - halts plasticity
```
61
decline in gray matter thickness
synaptic pruning
62
increase in white matter volume
due to increased myelination
temporal and regional variability in myelination and/or white matter integrity
different white matter tracts develop at different rates
develops in a rostral to caudal fashion = posterior/inferior areas underlying earlier-emerging sensory functions myelinate and prune earlier
antieror/superior areas mediating later-emerging higher order executive processes myelinate and prune later
63
development of the frontal lobes
last part of the brain to become myelinated
| responsible for cognitive control and anticipating consequences of our actions
64
functional MRI
measures increased blood flow (indirectly) during task performance
identify brain areas "active" during task performance
65
fMRI developmental changes
from more diffuse to more focal activity
| simple synaptic processing activate wider brain region in children vs. adults
66
resting state fMRI (sleep)
```
identify networks of brain regions that function together
ex: sensorimotor network
auditory network
visual network
salience network
```
67
intrinsic connectivity networks
increasing integration within intrinsic connectivity networks
increasing segregation between intrinsic connectivity networks
networks become highly focused and modular in adults
68
intrinsic connectivity networks in children
less modular and more interconnections than in adults
69
Etiology Fetal Alcohol Spectrum Disorders
Alcohol = teratogenic - exposure to embryo
70
facial dysmorphology in FAS
```
microcephaly
short palpebral fissures
thin upper lip
smooth philtrum
conically shaped skull
face develops most rapidly during the first trimester with adjacent brain regions (medial prefrontal)
```
71
Brian imaging in FAS
not diagnostic
| see affected areas (ex: corpus callosum)
72
gray matter thickness in FAS
increased gray matter thickness = less developed brain
| correlates with the degree of cognitive impairment
73
Autism diagnostic features
abnormal social behaviors
impaired communication
repetitive behaviors or restricted interests
*time course of development is altered*
74
Autism structural brain development
abnormal growth trajectory
larger brain in children with autism
early brain overgrowth followed by a reduced growth trajectory
average brain size larger in autism (associated with mental retardation)
75
amygdala development in ASD
begin with larger amygdalae which then develops at a reduced rate
76
abnormal growth of white matter in Autism
primary feature
later myelinating superficial radiations
later myelinating white matter compartments are overdeveloped in autism which earlier myelinating deep/bridging zones and longer range pathways are less developed
PROBLEM IN LONG-RANGE CONNECTIONS IN THE BRAIN
77
connectivity problem with autism
underconnectivity in long pathways (ex: corpus callosum; between Broca's and Wenickes area)
hyperconnections in short pathways
78
structural findings of cortical folding pattern abnormalities in autism
localized to the inferior frontal gyrus and inferior extents of the sensory and motor strips
79
abnormal activation in autism
low activation in the inferior frontal cortex in the pars opercularis when observing or imitating an emotional facial expression
correlates with measures of social development
80
abnormal reward circuitry in autism
involves nucleus accumbens
reward expectation strongly affects decision making
less reward response activation (impairment in early social development if don't respond to rewards)
81
ADHD brain abnormalities
fronto-stiatal network abnormalities
delayed forntal maturation (caudate and IFG are smaller in ADHD)
increased volume of gray matter = correlates to increased hyperactivity
82
response inhibition in normal children
depends on proper signaling between stratal reward structures and frontal cortex
83
dyslexia
learning disability = manifests as a difficulty with written language (particularly reading and spelling)
results from differences in how the brain processes written and/pr spoken langues
84
disorders associated with developmental abnormalities
```
autism spectrum disorders (ASD)
ADHD
Schizophrenia
Fetal Alcohol Syndrome
Drugs of abuse
```
85
risk of toxin exposure of CNS extends throughout pregnancy
CNS development continues through pregnancy (NOT JUST 1ST TRIMESTER like other teratogens affect organ systems)
86
CNS development in gestation
occurs though out all stages of gestation and continues in certain ways throughout early life
significant change occur in cerebral cortical structure and in myelination until 20 YO
87
CNS development @ 3rd wk gestation
begins in 3rd week = notochord induces overlying ectoderm to differentiate into neuroectoderm and form the neural plate
88
three primary vesicles of the developing brain
Forebrain (prosencephalon) --> telencephalon & diencephalon
Midbrain (mesencephalon) --> mesencephalon
Hindbrain (rhombencephalon) --> metencephalon & myelencephalon
89
five secondary vesicles
```
telencephalon
diencephalon
mesencephalon
metencephalon
myelencephalon
```
90
adult derivatives of telencephalon
cerebral hemispheres, preoptic area, basal ganglia
| lateral ventricles
91
adult derivatives of diencephalon
```
thalamus (dorsal)
hypothalamus
epithalamus
subthalamus
third ventricle
```
92
adult derivatives of mesencephalon
midbrain& cerebral aqueduct
93
adult derivatives of metencephalon
pons
cerebellum &
upper part of fourth ventricle
94
adult derivatives of myelencephalon
medulla & lower part of fourth ventricle
95
6th vesicle of brain
spinal cord = forms 31 pairs of spinal nerves
96
neural plate
gives rise to the neural tube and neural crest cells (thickening of ectoderm)
97
neural tube
forms all CNS neurons
98
notochord remnants
becomes nucleus pulpous of the intervertebral disc in adults
99
abnormal closures of the neural tube during weeks 3 & 4
spina bifida occulta = failure of bony canal to close
minigocele = meninges herniate through spinal canal defect
meningomyelocele = meninges and spinal cord herniate through canal defect
100
spina bifida incidence/cause
1/1000 births in US
low folic acid intake before conception and during pregnancy
elevates AFP in amniotic fluid and maternal serum
elevated acetylcholinesterase in amniotic fluid = confirmatory test
101
cellular processes of CNS development
```
generation of neurons & glia
cell migration
growth of connections
synapse formation (continues postnatally)
myelination (largely postnatal)
```
102
timing of CNS development
different processes are ongoing simultaneously in different CNS regions = toxins can affect one region & not another
103
generation of neurons & glia
neurons come from massive cell proliferation occurring primarily in periventricular germinal zones
104
periventricular regions contain neural stem cells that generate neuronal progenitors
multi potent self-renewing neural stem cells (embryonic, postnatal & adult) -->
committed neural progenitors = neuroblast (neurons) and glioblast (glia = astrocytes & oligodendrocytes)
105
differentiation of neural stem cells occurs in specific order
1st = neurons
2nd = astrocytes
3rd = oligodendrocytes
different processes are ongoing simultaneously in different regions
106
regulation of neural stem cell differentiation
protein growth factors
retinoic acid
transmitters (activity of neurons themselves)
107
effects of retinoic acid
accelerates the maturation of stem cells --> causes them to differentiate too early
TERATOGEN (acutane, vitamin A)
108
periventricular leukomalacia (PVL)
failure to develop white matter secondary to perivenrticular ischemia (26-36 weeks highest vulnerability)
premature infants at higher risk
leads to loss of oligodendrocyte progenitor cells in the periventricular tissue
injury can be asymmetric
109
multipotent neural stem cells persist in periventricular regions of the juvenile and adult CNS
can be propagated in tissue culture to give rise to neurons, astrocytes & oligodendrocytes
= giver rise to certain neurons and glia
unknown functions?
110
neuronal stem cells persist throughout life in the hippocampal dentate gyrus
new neurons are formed and incorporated continuously throughout juvenile adult & aged life
= equal numbers die so total is constant
111
role of new neurons in hippocampal dentate gyrys
formation of certain types of new memories
certain types of seizure disorders
behavioral effects of chemotherapy (due to toxic effects on adult neuronal stem cells & reductions in adult hippocampal neurogenesis)
112
cell migration in CNS
periventricular regions contain neural stem cells that generate neural progenitors --> migrate away to form different regions of the CNS
113
cell migration is guided by molecular cues on cell surfaces
adhesion molecule interations
| neuroblasts and neurons migrate along processes of radial glia
114
cell migration and formation of the cerebral cortex
layer VI forms first
migration by glia processes starting at bottom layer
occurs from 2 months to 8 months gestation
**exposure to environmental toxins that disrupt cell proliferation or migration affects specific neuronal populations based on time of exposure
115
radial glia guide neurons during development
then become astrocytes
116
effects of EtOH on neuronal development
causes premature transformation of radial glia into astrocytes = disrupts migrations of cortical neurons and disturbs cortical development
NEURONS CAN'T MIGRATE
117
growth of connections
neuronal connections are formed by axonal migration = achieved by growth cones
new membrane is added immediately behind the growth cone
direction of axonal migration is controlled by positive and negative guidance cues = attract or repulse growth cones (filopodia)
118
growth cone
new protein added at the back end of the axon
119
axonal migration
forms neural connections
| controlled by positive and negative guidance cues that attract or repulse growth cones
120
guidance cues
contact mediate attraction
contact mediated repulsion
chemoattraction = sets up diffusion gradient for attraction or repulsion
diffusion mediated attraction
diffusion mediated repulsion
*timing controlled by genetics = cues turned on or off
121
synapse formation (synaptogenesis)
synapses are highly specialized contacts between neurons that allow rapid signaling mediated by chemical ligand- receptor interactions
122
Mature synapses are complex structures with extraordinarily high densities of many different kinds of molecules:
requires many molecular interactions to hold synapses together
```
Adhesion
Structural
Receptors
Ion channels
2nd messenger
```
123
synaptogenesis
begins during first trimester
continues throughout gestation and juvenile development
is ongoing to some degree throughout adult life (& aging) where it is an essential part of synaptic plasticity
124
formation of synapses
can occur quickly (over minutes to hours)
begins with spine formation and interaction of adhesion molecules followed by accumulation of vesicles and other structural elements
125
synapse density in cerebral cortex
increases rapidly during 3rd trimester of gestation & first postnatal year
peaks in visual & auditory cortices ~ 1 year postnatal
peaks in frontal cortex at 4 to 5 years postnatal and is subject to “pruning” after peaking
126
peaks of synaptic density
occur at different times in different parts of the brain
prefrontal cortex= peaks at 4-5 YO then starts to be pruned
visual and auditory cortex peak earlier
127
synaptic formation and oligodendorcytes & myelination
continue through childhood and teenage development
| pruning and myelination
128
myelination
CNS myelination achieved by oligodendrocytes = derive from periventricular progenitors and migrate to where they are active
VERY FEW AXON TRACTS ARE MYELINATED AT BIRTH
129
most myelination occurs after birth and proceeds until the end of the teenage years
many developmental milestones correlate with myelination (walking, talking)
disturbances in myelination = functional defects
130
assessment of myelination in viv during childhood
MRI
131
total white volume vs. total gray matter volume throughout life
white matter increases
cortical gray matter decreases = pruning (losing synapses) = neurons take up less space = cortical thinning during childhood and adolescence
