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Anxiety Disorders, Autistic Disorder,
Attention-Deficit/Hyperactivity
Disorder, and Stress Disorders
Chapter 17
Copyright © Allyn & Bacon 2010
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
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Anxiety Disorders
Autistic Disorder
Attention-Deficit/Hyperactivity Disorder
Copyright © Allyn & Bacon 2010
ANXIETY DISORDERS
 Anxiety – chronic fear that persists in the
absence of any direct threat
 Anxiety disorder – when anxiety interferes
with normal functioning
Accompanied by physiological symptoms –
tachycardia, hypertension, sleep disturbances,
nausea, etc.
 Most prevalent of all psychiatric disorders
ANXIETY DISORDERS
 17% of people suffer from an AD
throughout life
 Females:males = 2:1
 Heritability estimates
30-50%
 No specific gene(s) have been linked to
anxiety disorders
Anxiety Disorders
 Panic Disorder
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

episodic periods of symptoms such as shortness of breath, irregularities in
heartbeat, and other autonomic symptoms, accompanied by intense fear.
Anticipatory Anxiety – a fear of having a panic attack; may lead to the
development of agoraphobia.
Prevalence – 3-5%
 Generalized Anxiety Disorder
•
•
Excessive anxiety and worry serious enough to cause disruption in one’s life
Prevalence - 3%
 Social Anxiety Disorder
•
•
•
Excessive fear of being exposed to the scrutiny of other people that leads to
avoidance of social situations in which the person is called upon to perform
Prevalence – 5%
Men = women
ANXIETY DISORDERS
 Possible Causes:
•
Variations in the BDNF
•
Val66Met allele of the BDNF gene impairs extinction of conditioned fear in animals and humans,
atypical activity of frontal cortex-amygdala circuitry (decreased activity of vmPFC during extinction).
 Functional imaging studies – amygdala, cingulate, PFC, insular cortices are
involved in anxiety disorders
 Increased activity in amygdala
Phan et al. (2005)
• People with social anxiety disorder showed increases in the activation of the
amygdala when they looked at pictures of faces with angry, disgusted, or
fearful expressions
• Activation of the amygdala was positively correlated with severity of people’s
symptoms
Activation of vmPFC suppressed amygdala activity in controls, but not in those with
anxiety disorders
Increased activity in amygdala and insular cortex in people with high levels of anxiety
(not diagnosed).
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•
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ANXIOLYTIC DRUGS
2 Classes
Serotonin Agonists
Benzodiazepines
Librium
Valium
SSRIs
Buspirone
5HT1A
Receptor
BENZODIAZEPINES
 Prescribed for anxiety, hypnotics,
anticonvulsants, muscle relaxants
 Most widely prescribed psychoactive drug in
NA
~10% of adult NA
BENZODIAZEPINES ACT ON GABAA RS
BDZs are GABA
agonists:
 bind
to GABAA
receptor at a
different site than
GABA (unknown)
 increase action of
GABA (inhibition)

Amygdala contains
high concentration
of GABAA receptors
BENZODIAZEPINES
 Side effects
Sedation, ataxia, tremor, nausea, withdrawal – rebound
anxiety
 Highly addictive
GABAA AGONISTS




Chemicals that active one of
the known sites (neurosteroid
site) also increase GABAA
activity.
During anxiety attacks
synthesis of neurosteroids (&
activity of GABAA receptor is
suppressed).
XBD173 (drug that increases
neurosteroids) and thus,
activity of GABAA receptor
Reduces panic, no sedation
or withdrawal
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SEROTONIN AGONISTS FOR ANXIETY
 Buspirone – selective agonist at 5-HT1A
receptor
Main advantages over benzodiazepines:
Produces anxiolytic effects without producing
ataxia, muscle relaxation, & sedation
Side effects – dizziness, nausea, headache,
insomnia
 SSRIs
ANXIOLYTICS
 D-cycloserine – indirect NMDA agonist
•
•
•
In conjunction with cognitive behavioral therapy
Facilitated treatment of acrophobia, social anxiety,
panic disorder
Augments the ability of cognitive behavior therapy to
extinguish fear responses
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Anxiety Disorders
 Obsessive-Compulsive Disorder (OCD)
•
A mental disorder characterized by obsessions and
compulsions.
• Obsessions – unwanted thought or idea with which a
person is preoccupied.
•
•
Concern or disgust with bodily secretions, dirt, germs, etc, fear
that something terrible might happen, need for symmetry, order,
or exactness
Compulsion – feel that one is obliged to perform a
behavior, even if one prefers not to do so
•
4 categories: counting, checking, cleaning,
avoidance
Prevalence: 1-2%
Females > males (slightly)
Begins in young adulthood
OCD
 Possible Causes:
Greater concordance for OCD in monozygotic than dizygotic
twins
• Associated with Tourette’s syndrome
• Neurological disorder characterized by tics and
involuntary vocalizations and sometimes by compulsive
uttering of obscenities and repetition of the utterances of
others
• Brain damage
•
Basal ganglia, cingulate gyrus, PFC
• Beta-hemolytic streptococcal infection
Immune system attacks and damages tissues
•
Copyright © Allyn & Bacon 2010
15
OCD
 Treatment
•
Cingulotomy – surgical destruction of specific fiber bundles in the
subcortical frontal lobe, including the cingulum bundle (PFC with
limbic cortex) and a region that contains fibers that connect the
BG with PFC
•
Capsulotomy – destroys fiber bundle (internal capsule) that
connects the caudate with the mPFC
•
DBS of BG or fiber tracts
•
Drugs:
•
•
5-HT reuptake blockers (5-HT agonists)
D-cycloserine
•
Facilitated extinction of the maladaptive thoughts and behaviors
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AUTISM - HISTORY
 Bleuler- 1910 autismus - 1st coined term even though
defining symptoms of schizophrenia
 Hans Asperger 1938 - described autistic psychopaths
Asperger’s syndrome
 Leo Kanner 1943 (infantile autism)
 Mid 1900’s - due to mother neglect
 1960’s, autism established as a separate syndrome
lifelong, separate from schizophrenia & mental retardation, benefited
by parental involvement in therapy
 Even up to 1970’s a genetic connection was not
established.
one of most heritable psychiatric conditions
PREVALENCE
 Estimated 1 in 156 in Canada in 2007 but in
Newfoundland
1 in 144 (2007)
1 in 135 (2008)
 More than 50% are diagnosed before kindergarten
 Numbers seem to be increasing
Better diagnostic criteria or actual increase?
 Males:females – 4:1
PERVASIVE DEVELOPMENTAL DISORDERS
 Autism
 Rett syndrome
Genetic neurological syndrome in girls (arrest of normal brain development)
 Asperger syndrome
speech is not delayed and IQ is at least 70
 Childhood disintegrative disorder
Normal intelligence and social behavior, then sever regression into autism (around ages
2-10 years)
 PDD not otherwise specified (PDD-NOS).
diagnosed if a child has some symptoms of PPD but not enough to meet specific criteria
of ASD.
Social
Behaviors
Autism Spectrum
Disorder
Communication
Repetitive
Behaviors
AUTISM
 Most have some abilities preserved – rote
memory, ability to complete jigsaw puzzles,
musical ability, artistic ability
 Savants – intellectually handicapped individuals
who display specific cognitive or artistic abilities
 ~1/10 autistic individuals display savant abilities
 Perhaps a consequence of compensatory
functional improvement in the right hemisphere
following damage to the left
Copyright © 2006 by Allyn and Bacon
AUTISM
 Learning disability (in about 70% of cases)
 Epilepsy (in about 30% of cases)
POTENTIAL CAUSES OF ASD- GENETICS
 Siblings of the autistic have a 5-10% chance of
being autistic
 70-90% concordance rate for monozygotic twins
 Likely due to an interaction between mutations in
several genes or between environment and genes
Neuroligins, neurexins, shank3 genes
A
large fraction of autism may result from
spontaneous alterations in genes at meiosis that
spontaneously duplicate or delete a gene (may be
heritable but not inherited).
POTENTIAL CAUSES OF ASD- GENETICS
 Defect in some genes lead to autism
when fetus is exposed to certain
environmental factors.
 Most candidate genes encode
proteins involved in neural
development and function
NEUROLIGINS: POSTSYNAPTIC CELL ADHESION
MOLECULES BINDING NEUREXINS
From Zoghbi, Science 2003
NEUROLIGINS AND THEIR BINDING PARTNERS

NL4
10 different mutations

NL3
Single mutation (the Arg451Cys substitution)

5 different larger deletions of X-chromosomal DNA that includes the NLGN4
locus were detected in patients with autism

NRXN1 – extracellular binding protein
7 point mutations, 2 distinct translocation events and 4 different large-scale
deletions

SHANK3 - an intracellular scaffolding protein that binds indirectly to NLGNs
through PSD95
18 point mutations were detected in the SHANK3 gene in patients with autism,
Terminal 22q deletion syndrome is a frequent occurrence that shows autistic
features that have been correlated with the absence of SHANK3, which is
normally localized to this chromosome.
NEUROLIGINS AND AUTISM
1. Non-symptomatic carriers were detected in the same families in
which the patients with the mutations were found.
SHANK3 point mutations in particular were often observed in non-symptomatic
siblings
 These mutations may only increase the chance of autism rather
than actually causing it.
2. The same mutations can be associated with different phenotypes
in different people.
Microdeletion in NLGN4 was found to cause severe autism in one brother but
Tourette's syndrome in the other
 Is 'autism' observed in patients with mutations in these genes
actually autism?
 Is autism qualitatively distinct from other cognitive diseases, as
opposed to being a continuum of cognitive disorders?
NEUROLIGIN ANIMAL MODELS
 NL3 Human mutation knock-in mouse
Selective deficit in social interaction
 NL4 knockout mice
Selective deficit in social interaction
Time in Interaction (s)
175
*
150
125
100
75
50
Social
POTENTIAL CAUSES OF ASD- GENETICS
Rett Syndrome
•
Mutation in the sequence of a single gene can cause Rett
syndrome. (MeCP2)
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•
•
After a period of normal development, sometime between 6
and 18 months, autism-like symptoms begin to appear.
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•
•
•
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Affects almost exclusively females,
1 in 10,000 to 15,000.
Mental and social development regresses—she no longer responds
to her parents and pulls away from any social contact.
If she has been talking, she stops
She cannot control her feet
She wrings her hands.
Some of the problems associated with Rett syndrome can be
treated. Physical, occupational, and speech therapy can help
with problems of coordination, movement, and speech
POTENTIAL CAUSES OF ASD-ENVIRONMENTAL
•
Prenatal exposure to:
•
•
•
•
thalidomide (morning sickness),
valproic acid (anticonvulsant) or
rubella infection in the mother
these mainly act in 1st 8 wks
•
Postnatal exposure to MMR:
• Parents often first become aware of autistic symptoms around
the time of vaccinations (MMR) and so a great deal of
speculation surrounded thiomersal (preservative having
mercury) as causative in ASD. However, overwhelming
evidence of properly controlled studies found no connection.
Authors of paper were found guilty of dishonesty by UK
General Medical Council, journal retracted claims (The
Lancet)
•
Several other environmental factors have been investigated as
potential causes including
• smoking, PCBs, & solvents.
POTENTIAL CAUSES OF ASD - ENVIRONMENTAL
 Thalidomide – given early in pregnancy –
increases chance of autism
•
•
Indicates neurodevelopmental error occurs within 1st
few weeks of pregnancy when motor neurons of the
cranial nerves are developing
Consistent with observed deficits in face, mouth, and
eye control
 Anomalies in ear structure indicate damage
occurs between 20 and 24 days after conception
Copyright © 2006 by Allyn and Bacon
NEUROANATOMICAL FINDINGS
•
•
Brain Size
• Smaller at birth, grows abnormally, 2-3 years of age – 10% larger
• Growth slows, 1-2% larger by adolescence
• Frontal & temporal cortex
• Amgydala – larger by age 4, normal in adulthood but with less
neurons
Brain Abnormalities
• White matter
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•
•
Decreased activity in fusiform face area in response to face stimuli
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•
Increased volume of short-range axons
Normal volume of long-range axons
May be due to lack of interest in faces
Increased volume of the caudate
•
Similar to OCD
NEUROCHEMICAL ABNORMALITIES
 Autistic children have low levels of oxytocin
 Oxytocin – peptide that serves as a hormone
and neuromodulator, facilitates pair bonding
and increases trust and closeness to others
 Oxytocin can improve sociability of people
with ASD
Copyright © Allyn & Bacon 2010
34
MIRROR NEURONS

Neurons located in the frontal lobe (premotor area) appear to be active when
monkeys observe others performing functions- social cognition areas


May be involved in our ability to understand what people are trying to do and to empathize
with their emotions
Areas of the cortex that normally
display fMRI activity when healthy
subjects observe others performing
tasks are not active in autistic patients
TREATMENTS
 Intensive behaviour early intervention for at least 2 yrs
during preschool years results in improved outcomes.
 Screening tests are available
 There is no single best treatment of ASD but most
respond best to highly structured, specialized programs
 Some of the best programs try to reduce inappropriate
behavior and increase communication, learning and
appropriate social behavior.
 Some types of drugs help
IS IT A MEDICAL PATHOLOGY?
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Some people with the condition do not consider it a
problem, just another way of ‘being’
Some who have ASD do not believe it needs a ‘cure’
Eg. Donna Williams & Temple Grandin
ART WORK BY DONNA WILLIAMS
Senses
Teddy Bear
Before
Stealing the moon
Music of Beingness
TEMPLE GRANDIN
(ASPERGER SYNDROME)
http://www.youtube.com/watch?v=2o6KYIw2yww
Does this go contrary to the
idea that people with ASD
have a deficit in empathy?
Temple designed a humane way to guide
cows to a slaughterhouse
http://www.templegrandin.com/
Attention-Deficit/Hyperactivity Disorder

Description



A disorder characterized by uninhibited responses, lack
of sustained attention, and hyperactivity.
Most common behavior disorder in childhood
Diagnosis of ADHD:

6 or more of 9 symptoms of inattention


6 or more of 9 symptoms of hyperactivity and impulsivity


ie. often had difficulty sustaining attention in tasks of play
ie. often runs about or climbs excessively in inappropriate situations
Persisted for at least 6 months
Copyright © Allyn & Bacon 2010
ADHD
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Symptoms can vary
4-5% of grade school children
Boys:girls, 10:1, adulthood, 2:1
60% of children show disorder in adulthood
(develop antisocial personality disorder and
substance abuse)
 Associated with: aggression, conduct disorder,
learning disabilities, depression, anxiety, low selfesteem
41
ADHD
 Treatment: methylphenidate (ritalin) – inhibits
reuptake of DA
Copyright © Allyn & Bacon 2010
42
ADHD
 Possible Causes:
 Estimated heritability 75-91%
 Symptoms are due to: a delay of reinforcement
gradient that is steeper than normal
•
Deficiencies in DA transmission in brains of ADHD increase
the steepness of their delay of reinforcement gradient
• Immediate reinforcement is even more effective, but even
slightly delayed reinforcement loses its potency.
Copyright © Allyn & Bacon 2010
43
Figure 17.9 Delay of Reinforcement Gradients in ADHD
Copyright © Allyn & Bacon 2010
ADHD
 Damage to PFC – distractibility, forgetfulness,
impulsivity, poor planning and hyperactivity
 Low levels of DA in PFC
 Methylphenidate increases level of DA (and NE) in
PFC
 Abnormalities in striatum (connections to PFC)
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SUMMARY: GENES & MENTAL ILLNESS
 There are no genes for psychiatric disorders
in the sense that there are genes for eye
color.
 No known gene is either necessary or
sufficient to produce mental illness.
However, this is different for one particular neurological
disorder.
 Instead, there are many susceptibility genes