Transcript Lecture 15A

Videos
• TED talk Sherwin Nuland tells about electroshock
therapy:
http://www.ted.com/talks/sherwin_nuland_on_elec
troshock_therapy
• Eleanor Longden, a research psychologist, talks
about her struggles with Schizophrenia when getting
her Master’s degree in Psychology:
https://www.ted.com/talks/eleanor_longden_the_v
oices_in_my_head
Nature and Nurture
Figure 1.13: Twin Studies of Behavioral and Medical Disorders
Concordance = the presence of the same trait in both members of a pair of twins
• Heritability: Percentage of variation in a
characteristic that is attributed to genetics:
– Identical twins share nearly 100% of their genes.
– Fraternal twins share development environment. Fraternal twins are,
essentially, two ordinary siblings who happen to be born at the same
time, since they arise from two separate eggs fertilized by two separate
sperm, just like ordinary siblings.
Diseases of CNS
• Presented in the following order: from clear
etiology to less clear
• Part of neuroscience: neuropsychology
Stroke
accounts for 87%
of all stroke cases
• Signs: an inability to move
or feel on one side of the
body,
– problems understanding or
speaking,
– feeling like the world is
spinning,
– loss of vision to one side.
– Recall: Jill Bolte Taylor TED
talk
• Stroke is the second most frequent cause of
death after coronary artery disease, accounting
for 6.4 million deaths (12% of the total).
• Most commonly, strokes occur as a result of damage to the
middle cerebral artery of the brain. Predict the symptoms?
• Patient with damage here often develop a paralysis on one side.
• Rarely the damage is in the region of posterior cerebral artery, affecting the
occipital lobe. Predict the symptoms?
• Visual system damage such as visual agnosia in pilot John’s. Note John did
not show any paralysis, so his doctors were in denial of stroke for many
weeks
• accounts for 87% of all stroke cases
• An ischemic stroke, if detected within three
hours, may be treatable with a medication
that can break down the clot.
• Keep talking to the person: sensory
stimulation was shown to be neuroprotective
CT scan or MRI scan
• Bleeding may occur due to a brain aneurysm
• Diagnosis is typically with medical imaging such
as a CT scan or MRI scan
• Rehabilitation can take months or years (E.g. Jill
Bolte Taylor, my friend RH)
Hemorrhagic stroke
• no ischemia initially,
• mostly blood penetrates around
brain tissues and compresses them.
• Ischemia is a secondary phenomenon,
from compression.
• Depends on volume of blood –
larger hematomas in basal ganglia
or subcritical white matter do not recover well, often fatal.
• If small, then blood resorbes overtime, cells that were only
partially damaged can recover.
• White matter tracts (not cells) can get rewired overtime d/t
feedback loops from damaged areas back to cortex =
plasticity still, but "reverse" if you will. "I am not working
here downstream, let's fix this upstream..." :)
•
•
•
•
•
A degenerative disorder of CNS
One small nucleus in brainstem: Substantia nigra.
Dopamine-generating cells in the substantia nigra
die due accumulation of the protein alphasynuclein. This insoluble protein accumulates inside
neurones forming inclusions called Lewy bodies.
Lewy bodies first appear in the olfactory bulb,
medulla oblongata and pontine tegmentum, with
individuals at this stage being asymptomatic. As the
disease progresses, Lewy bodies later develop in
the substantia nigra, areas of the midbrain and
basal forebrain, and in a last step the neocortex.
Prevalence: 1 in 300.
Initially symptoms are movement-related:
Parkinson’s
disease
– shaking, rigidity, slowness of movement and difficulty
with walking and gait. What part of the brain controls
habitual movements?
– Decreasing control of basal ganglia Patients are
describing their walking experience similar to “going to
England and renting a car. You can drive but it takes a lot
of conscious awareness to control the driving”
•
•
•
Later, dementia and depression; sensory, sleep and
emotional problems.
Famous patients: Michael J Fox:
https://youtu.be/ECkPVTZlfP8 (do not show in
class)
Clear risk factors: insecticides, pesticides, such as
rotenone or paraquat, and herbicides
(weedkillers), such as Agent Orange and ziram
Basal
Ganglia
A Lewy body (stained brown) in
a brain cell of the substantia
nigra in Parkinson's disease. The
brown color is positive
immunohistochemistry staining
for alpha-synuclein.
Parkinson Disease
• Substantia nigra continuously drips Dopamine onto basal ganglia –
• What is the information in that continuous dripping of dopamine?
• It is allowing the basal ganglia to continue stimulating movement without
freezing.
• The substantia nigra normally inhibits freezing and other fearful behavior in
mammals via its connections with the superior colliculus.
• Lack of stimulation from substantia nigra  Lack of inhibition of superior
colliculus visual responses to distractors appearing in peripheral vision 
Freezing to harmless distractors.
• Parkinson Disease sufferers are often freezing at a doorway or another
confined space when there are distractors detected by superior colliculi.
Nature and Nurture
Figure 1.13: Twin Studies of Behavioral and Medical Disorders
Concordance = the presence of the same trait in both members of a pair of twins
Parkinson’s disease treatment
• Levodopa (L-DOPA) has been the
most widely used treatment for over
30 years. L-DOPA is converted into
dopamine in the dopaminergic
neurons.
• Since motor symptoms are produced
by a lack of dopamine in the
substantia nigra, the administration
of L-DOPA temporarily diminishes the
motor symptoms.
• Only 5–10% of L-DOPA crosses the
blood–brain barrier. The remainder is
often metabolized to dopamine
elsewhere, causing a variety of side
effects including nausea.
Deep-brain stimulation
•
•
•
•
•
Electrical stimulation
significantly reduces
tremor
Deep brain stimulation
involves implanting
electrodes within certain
areas of the brain.
Electrodes produce
electrical impulses
A wire that travels under
the skin connects this
device to the electrodes in
the brain.
There are a few sites in the
brain that can be targeted
to achieve differing results,
so each patient must be
assessed individually, and
a site will be chosen based
on their
needs. Traditionally, the
two most common sites
are the globus pallidus
interna in basal ganglia
and the subthalamic
nucleus .
Alzheimer's disease
• a chronic neurodegenerative
disease that usually starts slowly
and gets worse over time
• accounts for 65% of cases of
dementia
• early symptom is short-term
memory loss
• As the disease advances: problems
with language, disorientation,
mood swings, loss of motivation,
not managing self care
amyloid beta
peptides
• Plaques (~50µm in size)
are extracellular
deposits of amyloid
beta peptides (36–43
amino acids) in the
grey matter
of the brain
• Neurofibrillary tangles are
formed by a microtubuleassociated protein known
as tau, causing it to
aggregate in an insoluble
form.
amyloid beta
peptides
Deep Sleep
connection
• More amyloid beta peptides  less deep
sleep  less long-term memory
• amyloid beta peptides first accumulates in
the medial PFC, one of the regions that
controls deep sleep
• No deep sleep  no long term memory
formation
Nature and Nurture
Figure 1.13: Twin Studies of Behavioral and Medical Disorders
Concordance = the presence of the same trait in both members of a pair of twins
Mad cow disease – prion disease
•
•
•
•
•
A prion is a protein that can fold in multiple, structurally distinct
ways, at least one of which is transmissible to other prion
proteins.
It is this form of replication that leads to disease that is similar to
viral infection.
The word prion, coined in 1982 by Stanley B. Prusiner, is derived
from the words protein and infection, in reference to a prion's
ability to self-propagate and transmit its conformation to other
prions.
Bovine spongiform encephalopathy (also known as "mad cow
disease") (UK  energy crisis of 1970s  feeding untreated
brain tissue to cows  epidemic)
Kuru - transmitted among members of the Fore
tribe of Papua New Guinea via funerary cannibalism
(particularly eating the brain of deceased relatives.
Studied by Daniel Gajdusek who was awarded the
awarded the Nobel Prize in 1976. Three stages of
Kuru:
–
–
–
–
unsteady stance, decreased muscle control, tremors,
deterioration of speech
the patient is incapable of walking, loss of muscle
coordination and severe tremors; the victim is
emotionally unstable and depressed, yet has
uncontrolled sporadic laughter.
the patient is incapable of sitting, no muscle
coordination, is unable to speak, is incontinent,
difficulty swallowing.
An infected person usually dies within three months
to two years after the first symptoms, often because
of pneumonia.
Amyotrophic lateral sclerosis
• Also known as Charcot disease, Lou Gehrig's
disease in US and motor neuron disease in UK.
• Lou Gehrig (1903 – 1941) was a baseball player
who played 17 for the New York Yankees, from
1923 through 1939. In 1939 he was diagnosed
with ALS and died two years later.
• ALS is characterized by gradually worsening
muscle weakness. This results in difficulty
speaking, swallowing, and eventually breathing.
• The defining feature of ALS is the death of both
upper and lower motor neurons in the motor
cortex of the brain, the brain stem, and the
spinal cord. Motor neurons accumulate some
proteins (due to defects in protein degradation)
in their cell bodies and axons and die.
• In 90% of case the cause is unknown. In 10%
ALS is due to inherited mutation.
Epilepsy
• Epilepsy (from the Ancient
Greek meaning "to seize") is
a group of neurological
disorders characterized by
epileptic seizures.
Prevalence: 1 in 100
• Epileptic seizures are
episodes that can vary from
brief and nearly
undetectable to long
periods of vigorous shaking.
• Often brought on by factors
such as lack of sleep, stress
or flickering light among
others.
• In epileptic seizures a
group of neurons
begins firing in an
abnormal, excessive,
and synchronized
manner.
• Patient HM.
• Gazzaniga – corpus
callosum resection.
• The Brain: Teaching
Modules. (1997).
http://www.learner.o
rg/vod/vod_window.
html?pid=1598
Nature and Nurture
Figure 1.13: Twin Studies of Behavioral and Medical Disorders
Concordance = the presence of the same trait in both members of a pair of twins
Febrile seizure
• Febrile seizure = An epileptic
seizure associated with a high
body temperature but without
any serious underlying health
issue.
• They most commonly occur in
children between the ages of 6
months and 5 years.
• Most seizures are less than five
minutes in duration and the
child is completely back to
normal within sixty minutes of
the event.
Depression
• Pervasive and persistent low mood
• A loss of interest or pleasure in normally
enjoyable activities.
• The lifetime prevalence of
major depression is 20-26% for women
and 8-12% for men
• In the United States, around 3.4% of
people with major depression commit
suicide
• Aristotle once claimed that "there is no
great genius without a mixture of
madness.”
• A study of more than 700,000 adults
showed that those who scored top
grades at school were four times more
likely to have periods of depression than
those with average grades.
• Depression vertex is often driven
by mental synthesis
The Scream by Edvard Munch
Depression treatment:
Psychoanalysis
• Deep-brain structures, basal ganglia and
amygdala, regulate habitual emotional and
motor responses. The basal ganglia hold
sway when we ride a bicycle and also when
we indulge in common habits, such as those
that make us long for that ice cream or a
chocolate.
• basal ganglia control our behavior during
time of stress.
• furthermore, basal ganglia are not under the
direct conscious control.
• During psychoanalysis subject talks about
their emotional memories and habits.
• The memories are pulled from the basal
ganglia and amygdala, unpacked and placed
under the conscious control of the prefrontal
cortex.
• Now the experiences can be modified and
rewritten into the memory. This memory
modification can benefit the patient’s wellbeing by changing their habitual behavior.
blue=basal ganglia
yellow=hippocampus
green=corpus callosum
Depression
treatment:
Antidepressants
• Selective serotonin reuptake
inhibitors (SSRIs) (e.g. Prozac)
• Monoamine oxidase inhibitors block
monoamine oxidase, an enzyme
that breaks down monoaminergic
neurotransmitters (5-HT, DA, NE,
EPI). This increase neurotransmitter
concentration in synaptic cleft.
• Monoamine oxidase inhibitors are
one of the major classes of drugs
prescribed for the treatment of
depression
• (Tobacco is mild MOA inhibitor –
many people self medicate with
tobacco)
• Before introduction of
antidepressants in 1970s, a very
depressed patient is a common
occurrence is a hospital… not any
more
Transcranial magnetic stimulation
• MRI test  complete
depression relieve
• A large electromagnetic
coil is placed against
near the forehead.
• The electromagnet used
in TMS creates electric
currents that stimulate
nerve cells in the PFC.
Depression treatment: electroshock
• TED talk Sherwin Nuland
tells about electroshock
therapy:
http://www.ted.com/talks/s
herwin_nuland_on_electros
hock_therapy
• Significant memory loss
• Deep brain stimulation
involves implanting
electrodes within
certain areas of the
brain.
• Electrodes produce
electrical impulses
• A wire that travels
under the skin
connects this device to
the electrodes in the
brain.
• A number of
neuroanatomical
targets:
– the subgenual
cingulate gyrus
– nucleus accumbens
– ventral
capsule/ventral
striatum
– inferior thalamic
peduncle
– the lateral habenula
Deep-brain stimulation
Depression is common in intellectuals
• If you think you are falling into depression vertex:
– Treat yourself with travel, skydiving and other pleasant
and meaningful experience
– Exercise vigorously for at least 30 consecutive minutes
every day.
– Avoid all stimulants, avoid caffeine completely (no tea,
no green tea, no decaf)
– Yoga
– Organic gardening
– Acupressure and acupuncture
– Solve the problem that is leading to stress!
• Most importantly: millions of other intellectuals
passed through periods of depression. It is normal.
Any such period will pass and you will come out
stronger and wiser!
Psychosomatic
Panic attack 
massage H7
• Psychosomatic means mind (psyche) and body (soma).
• A psychosomatic disorder is a disease which involves both
mind and body.
• Some physical diseases are particularly prone to be made
worse by mental factors such as stress and anxiety.
• Mental illnesses are influenced by the mind by definition
• Spectrum: from diseases that clearly psychosomatic:
Panic attacks (heart palpitations, dizziness, shortness of
breath – feels like a heart attack) to the least
psychosomatic, like Multiple Sclerosis
• Most mental diseases are in between
Drug addiction
• Is it a disorder?
• You can treat drug addiction as a disorder
• patients need to unlearn the euphoria /
reward system activation associated with the
drug.
• Current strategy for opioid abusers:
methadone (a synthetic opioid)
• Better strategy: extended release naloxone
(opioid antagonist)
Schizophrenia
• Eleanor Longden, a research psychologist, talks about
her struggles with Schizophrenia when getting her
Master’s degree in Psychology:
https://www.ted.com/talks/eleanor_longden_the_voice
s_in_my_head
• Prevalence: 1 in 100
• Symptoms: Delusions - beliefs held with strong
conviction despite superior evidence to the contrary;
unclear or confused thinking; auditory hallucinations.
• Strange time of onset: late adolescence and early
adulthood. Probably associated with all that anxiety that
sets in during puberty – evolutionarily primates are
always (usually females) left their parent’s tribe and
joined another tribe to avoid inbreeding.
• Treatment of Schizophrenia: antipsychotic medications
(e.g. chlorpromazine), which primarily suppresses
dopamine receptor activity.
• reduced myelination  not enough synchronicity?
John Nash, a
mathematician,
winner of the 1994
Nobel Prize for
Economics. His life
was the subject of
the 2001 Academy
Award-winning film
A Beautiful Mind.
2016 finding of gene responsible for
too much of "synaptic pruning"
• There have been hundreds of theories about schizophrenia over the years, but
one of the enduring mysteries has been how three prominent findings related
to each other:
– the apparent involvement of immune molecules,
– the disorder's typical onset in late adolescence and early adulthood, and
– the thinning of gray matter seen in autopsies of patients.
• data from about 29,000 schizophrenia cases, 36,000 controls and 700 post
mortem brains
• person's risk of schizophrenia is dramatically increased if they inherit variants
of a gene important to "synaptic pruning"
• synaptic pruning is normal reduction of synapses during adolescence.
• The C4 gene is located on chromosome 6 along with numerous other genes
involved in the immune system, which clears out pathogens and similar cellular
debris from the brain.
• one of C4's variants, C4A, was most associated with a risk for schizophrenia.
• In patients with schizophrenia, a variation in a single position in the DNA
sequence marks too many synapses for removal and that pruning goes out of
control. The genes involved coat the neurons with "eat-me signals. And they're
gobbled up.“
• The result is an abnormal loss of gray matter.
Nature and Nurture
Figure 1.13: Twin Studies of Behavioral and Medical Disorders
Concordance = the presence of the same trait in both members of a pair of twins
Lobotomy
• Over 70,000 patients worldwide
(between 1935 and 1986) (40,000 in
the USA)
• Pioneered by the Portuguese
physician António Egas Moniz, who
received the Nobel Prize in 1949 "for
his discovery of the therapeutic value
of leucotomy [lobotomy] in certain
psychoses.
• According to the Psychiatric
Dictionary published in 1970:
“Prefrontal lobotomy was found of
value in the following disorders, listed
in a descending scale of good results:
affective disorders, obsessivecompulsive states, chronic anxiety
states and … schizophrenia”.
• Note connection to Mental Synthesis
Rosemary Kennedy:
Joseph Kennedy arranged
lobotomy for her at the age of
23, but it failed and left her
incapacitated permanently.
Neurodevelopmental diseases:
Attention deficit hyperactivity
disorder
• Definition “problems paying attention, excessive
activity, or difficulty controlling behavior which is
not appropriate for a person's age. These
symptoms begin by age six to twelve, are present
for more than six months, and cause problems in
at least two settings (such as school, home, or
recreational activities)”
• Who makes the decision?
• Treatment with stimulants: Retalin ~ cocaine;
Adderall ~ Amphetamine
• Better treatment with patience, exercise and diet
Down
syndrome
Autism
•
•
•
•
Neurodevelopmental disorder
Prevalence: 1 in 68 children
Male to female ratio = 4:1
The cost of autism to the US
is upwards of $35 billion per
year
• The cost of providing care for a
single
individual about $126 million.
Sensory overload
Repetitive activity
Lining things up
• Brain abnormalities in circuits processing faces  no
interest in face observation speech does not develop
• As a result, nearly 50% of children with Autism, do not
use language during the critical period.
• Without language they do not exhibit symbolic play, no
understanding of spatial prepositions or verb tenses 
do not acquire mental synthesis
• They often acquire some words after the end of critical
period, but too late for mental synthesis and full
syntactic language.
• These kids are at risk of mental synthesis disability
No syntactic language
No symbolic Play
Asynchronous
connections
Synchronous
connections
"stimulus
overselectivity“
in kids with ASD
• Consistent observation with autistic kids: when asked to pick
up the "red crayon under the table," the child with autism
often picks a "crayon" and ignores both its location and the
fact that it should also be red.
• This characteristic has been called "stimulus overselectivity"
or "tunnel vision“ or “lack of response to multiple cues.”
Why?
• Mental Synthesis theory explanation: since lacking mental
synthesis, the child cannot generate a mental image of the
“red crayon under the table”.
• The child will therefore pick up any available crayon, failing to
attend to the cues of color and location.
CURRENT APPROACH TO
LANGUAGE THERAPY:
“Give me the
red crayon from
under the table”
Step 2
“Give me the
red crayon”
Step 1
“Give me the
crayon”
Language therapy will
therefore include
exercises aimed at
training mental
synthesis
PROBLEM: pick up the "red crayon under the table” is a multimodal process
AUDITIRY
PROCESSING
MENTAL
RECOLLECTION
Audio memory of “crayon”
Visual recollection of
“crayon”
Audio memory of “red”
Visual
recollection
of “red”
Audio memory of “table”
Visual
recollection
of a “table”
MENTAL
SYNTHESIS
Mental Synthesis theory
prediction:
• Full infinite language:
1. Vocabulary
2. Mental Synthesis
Train mental
synthesis
separately!
• Developmental toys and puzzles are helpful;
• however, physical puzzles are always limited in
their range and adaptability.
ImagiRation is
developing
exercises on an
iPad disguised
as a game
Number of cues to attend to
ImagiRation therapy learning
steps are very small and gradual
Step 1
Step 5
Step 4
Step 3
Step 2
Attend to one
cue: shape
(moderate)
Attend to two
cues:
size & color
Attend to
three cues:
shape, size
& color
Attend to one cue:
shape (difficult,
outlines are
overlapping)
Attend to one
cue: shape
(easy)
Puzzles are increasing in difficulty gradually over time
Attend to many
visual cues
Exercises that require attending to only one cue. A: shape, B: size, C: color, D: pattern.
Examples of more difficult exercises that require attending to two cues simultaneously.
A: color and shape, B: color and size.
• Even more difficult exercise that require
attending to three cues simultaneously:
color, pattern, and size
• Examples of complex exercises that require
attending to a whole variety of visual cues
simultaneously
• Mental Imagery Therapy for Autism (MITA) clinical trial
started in 2016, currently over 15,000 kids
• MITA exercises  MITA therapy may trigger a domino
effect by boosting child's mental synthesis ability
• Mental synthesis + words  full language
• Full language  loss of ASD diagnosis
ImagiRation
exercises
Asynchronous
connections
Synchronous
connections
• A free download of the
complete book:
mobilereference.com/mind
• The neurobiology of
consciousness and
evolution of language – Fall
2016
• If you know any parent of a
child with autism, direct
them to MITA clinical trial:
ImagiRation.com
• Stop here
Neurodevelopmental diseases:
Microcephaly
• "Microcephaly" means "small brain"(from Ancient
Greek μικρός "small" and κεφαλή "head").
• Affected newborns generally have striking
neurological defects and seizures.
• Severely impaired intellectual development is
common, but disturbances in motor functions may
not appear until later in life
• People with Microcephaly were sometimes sold to
freak shows in North America and Europe in the
19th and early 20th centuries, where they were
known by the name "pinheads".
• A homozygous mutation in one of the microcephalin
genes causes primary Microcephaly.
Tay–Sachs
disease
• Tay–Sachs disease is caused by insufficient activity of the enzyme
hexosaminidase A that breaks down lipid (same lipids that are part of cell
membrane and myelin). Hexosaminidase A is primarily found in lysosome.
• When hexosaminidase A is no longer functioning properly, the lipids
accumulate in the brain and interfere with normal biological processes.
• Lack of enzyme causes a progressive deterioration of nerve cells and of
mental and physical abilities that begins around six months of age and
results in death around the age of four.
• There is no known cure or treatment.
Tay–Sachs disease
Tay–Sachs disease
• Tay–Sachs results from mutations in the HEXA gene on human
chromosome 15, which encodes a lysosomal enzyme.
• Tay–Sachs disease is an autosomal recessive genetic disorder,
meaning that when both parents are carriers, there is a 25% risk of
giving birth to an affected child with each pregnancy. The affected
child would have received a mutated copy of the gene from each
parent.
• In the United States, about 1 in 30 Ashkenazi Jews are a recessive
carrier.
• The incidence is approximately 1 in 320,000 newborns.
Current paradigm: children are
working with speech pathologists
Speech pathologists
improve speech
development.
However, speech
acquisition often happens
after the end of the
critical period for mental
synthesis acquisition.
Proposed paradigm: children are
working with speech pathologist
and ImagiRation puzzles
ImagiRation puzzles
promote mental synthesis
development.
When speech is acquired,
it complements mental
synthesis to result in full
syntactic language.
At least 50% of
children with autism
end up with a
significant impairment
of mental synthesis.
• Greater IQ
• Lower rate of
institutionalization
• Increased ability to go
to school with
neurotypical children
• Ultimately, increased
ability to live
independent
productive life.
•
•
•
•
Why do we read fairy tales to children?
Why do we encourage symbolic play?
Why do we get so many toys to our kids?
Because we want children to expand their mental
playground. We are teaching kids the techniques they
could use to exercise their neural networks into fine-tuned
synchronous connections.
• At the center of this process is the ability to use full
syntactic language.
Syntactic language
Symbolic Play
Asynchronous
connections
Synchronous
connections
•
•
•
•
•
50% of children with Autism,
Majority of children with Down syndrome,
Children with Pervasive Developmental Disorder,
Do not use full language during the critical period.
These kids are at risk of mental synthesis disability
Syntactic language
Symbolic Play
Asynchronous
connections
Synchronous
connections
• One of the main challenges of working with any
children exhibiting a significant language delay
is finding a way to provide them with the
necessary cognitive training outside the lowperforming speech-domain.
Non-linguistic
brain training
Asynchronous
connections
Synchronous
connections
Current
Research
a.
b.
c.
d.
e.
f.
ImagiRation puzzles
a.
b.
c.
d.
e.
f.
ImagiRation puzzles
5-alpha-reductase deficiency
syndrome (penis at 12)
testosterone
5α-dihydrotestosterone
• If you have an XY boy, but you bring him up as
a girl, do you get a grown-up girl?
• 5α-Reductase, an enzyme that converts
testosterone to 5α-dihydrotestosterone (DHT),
is missing.
• At birth: female external genitalia, no uterus
(due to Müllerian inhibiting factor)
• At puberty: increase in testosterone activates
DHS receptors causing a small penis to develop
• Study: male sexuality despite female
upbringing.
• Figure 4: 12 YOA; Fig 5 same boy at 19 YOA