Neurologically Speaking Part 3

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Neurologically SpeakingPart 3

• Martha S. Burns, Ph.D.
• September 2009

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Autism Spectrum Disorder is Genetic

• Autism spectrum disorders have a strong genetic
  bases
• autism susceptibility genes
• Copy number variations ( insertion or deletion of
  large DNA fragments) both inherited and
  idiosyncratic and other mutations
• Genetic syndromes
• But linking genes to specific language, social
  skill and repetitive behaviors will help drive
  interventions

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Abrahams and Geschwind (2008)Advances in autism
genetics on thethreshold of a new neurobiology

• Figure 1 Loci implicated in ASD etiology.
• Green bars correspond to genes that are observed
  to modulate autism spectrum disorder
• light green and dark green bars represent
  promising or probable candidate genes,
  respectively
• Red and yellow bars correspond to de novo losses
  and gains, respectively, that are observed in
  cases but not in controls

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Some of the genes regulate brain development

• Common genetic variants on 5p14.1associate with
  autism spectrum disorders Wang et al, Nature 2009
• For example - CDH9 and CDH10
• Are very important for the development of the
  obito-frontal cortex

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Structural Architecture of the Human Cortex
pre-natal to 16 years
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So what does this part of the brain do?
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Pre-frontal Lobes

• Ventromedial connected to limbic system
• Important in delayed gratification
• Empathy
• Dorsolateral
• Organization, planning, flexibility
• Working memory
• Processing speed

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Meeting of minds the medial frontal cortex and
social cognition.Amodio, DM and Frith, CD.
(2006) Nature Reviews Neuroscience 7, 268-277.
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Amodio et al. Nature Reviews Neuroscience 7,
268277 (April 2006) doi10.1038/nrn1884
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Amodio et al. Nature Reviews Neuroscience 7,
268277 (April 2006) doi10.1038/nrn1884
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Mindblind Eyes An Absence ofSpontaneous Theory
of Mind inAsperger Syndrome

• Atsushi Senju,Victoria Southgate, Sarah White,
  Uta Frith
• SCIENCE VOL 325 14 AUGUST 2009
• .

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Sally-Anne False Belief Task (FBT)

• (Sally) places a marble in a basket and leaves
  the room. In her absence, another character
  (Anne) moves the marble to a box. When Sally
  returns, children are asked where she will look
  for her marble.
• If children understand that Sallys actions will
  be based on what she believes to be true, rather
  than the actual state of affairs, they should
  answer that she will look in the basket, rather
  than the box.
• This correct answer requires the child to predict
  Sallys behavior based on her now false belief
• Children with autism fail the verbally instructed
  Sally-Anne false-belief task (FBT), whereas
  4-year-old neurotypical children pass, as do
  children with Down syndrome of similar verbal
  mental age

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Asperger Syndrome

• Despite still exhibiting atypical social features
  characteristic of autism, individuals of higher
  verbal ability, in particular those with Asperger
  syndrome, can pass such false-belief attribution
  tasks
• This has prompted the proposal that these
  high-ability individuals have acquired the
  ability to reason explicitly about false beliefs
  by compensatory learning, whereas difficulties in
  spontaneous mental-state attribution may
  nevertheless persist

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Limbic System

• Channeling emotion and motivation
• To behaviorally relevant motor acts, mental
  content and extrapersonal event
• Is accomplished through the paralimbic regions

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Eye-tracking task that has revealed the
spontaneous ability to mentalize in typically
developing infants
In familiarization trials, participants were
familiarized to an event in which (A) the puppet
placed a ball in one of two boxes, (B) both
windows were illuminated and chime sounded, and
(C) an actor reached through the window above
the box in which the ball was placed and
retrieved the ball. The participants were
familiarized to the contingency between (B) and
(C). In (D), the puppet moves the ball while the
actor is looking away. This operation induces a
false belief in the actor about the location of
the ball.
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Fig. 2 (A) Mean (/- SEM) DLS (19) and (B) the
ratio of the number of participants who made
correct first saccades in each group AS,
participants with Asperger syndrome (n 19) NT,
neurotypical participants (n 17). P lt 0.05
P lt 0.01. Dotted lines indicate chance level.
Statistical test used (A), t test (B),
binominal test.
A. Senju et al., Science 325, 883 -885 (2009)

Published by AAAS
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Conclusions

• results confirm indirect indications that
  individuals with Asperger syndrome have a
  persistent impairment in spontaneous mentalizing
• are also consistent with a previous finding that
  children with autism are more likely to give a
  correct verbal answer than a correct anticipatory
  look when asked to infer someones preference.

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The Limbic System

• Regulates emotions
• Through the frontal lobe connections as we
  mature
• We become conscious of our own emotions
• Then are able to interpret the emotions of others
  
• Perhaps largely through the mirror neuron system
  which leads to
• Compassion
• Empathy

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Emotional circuits
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Tuning the developing brainto social signals of
emotions

• Jukka M. Leppänen and Charles A. Nelson
• NRNS 1.09

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b Results showing that discrimination of
emotional expressions in bimodal (audiovisual)
stimuli emerges earlier than discrimination
of emotional expressions in unimodal auditory or
visual stimuli. c After habituation to happy
expressions on different faces, 7-month-old
infants could discriminate this expression from
fearful and angry expressions when the stimuli
were presented upright but not when they were
inverted
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Emotion-related neural systems (the amygdala and
the orbitofrontal cortex (OFC)) receive visual
information from cortical regions that are
involved in the visual analysis of invariant
and changeable aspects of faces (face-sensitive
regions in the fusiform gyrus and the posterior
superior temporal sulcus (pSTS)).
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Giacomo Rizzolatti, Maddalena Fabbri-Destro and
Luigi CattaneoMirror neurons and their clinical
relevanceNature Clinical Practice NEUROLOGY 2009
5(1)

• Mirror mechanism - neural system that unifies
  action perception and action execution
• Mirror mechanism is organized into two main
  cortical networks, formed by
• the parietal lobe and premotor cortices
• the insula and anterior cingulate cortex
• Role of the Mirror Mechanism - to provide a
  direct understanding of the actions and emotions
  of others without higher order cognitive
  mediation
• action understanding theory

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Giacomo Rizzolatti, Maddalena Fabbri-Destro and
Luigi CattaneoMirror neurons and their clinical
relevanceNature Clinical Practice NEUROLOGY 2009
5(1)

• Limited development of the mirror mechanism seems
  to determine some of the core aspects of autism
  spectrum disorders
• There is a recently demonstrated link between
  limited development of the mirror mechanism and
  that of some aspects of the motor system
• this suggests that rehabilitation in children
  with autism spectrum disorder should take into
  account both motor and cognitive strategies

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children with and w/o autism on fMRI while they
observed or imitated facial emotional expressions
(a). children with autism show reduced activity
in (MNS) lin the pars opercularis of the inferior
frontal gyrus. Thix correlated with the severity
of disorder
Iacoboni and Dapretto Redgrave Nature Reviews
Neuroscience 7, 942951 (December 2006)
doi10.1038/ nrn2024
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There are also perceptual deficits

• That interfere with ability to perceive pitch
  variations in voice that signal emotion, Russo
  and Kraus, 2008
• And perceive facial cues, Dalton et al
• And perceive human bodily movement

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Methods

• 12 children diagnosed with an Autism Spectrum
  Disorder
• 6 trained, 6 control
• Age matched (Trained9.171.47 years Control
  9.01.47 years, n.s.)
• Brainstem neurophysiology tests
• /da/ in quiet and background noise
• rising and falling /ya/ in quiet

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Pitch tracking and phase locking of F0 improved
AUT10
Pre
Post
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AUT10
Pre
Post
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Pitch tracking to the harmonics improved
AUT10
Post
Pre
Post
AUT16
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Kim M Dalton, Brendon M Nacewicz, Tom Johnstone,
Hillary S Schaefer, Morton Ann Gernsbacher, H H
Goldsmith, Andrew L Alexander  Richard J
Davidson

• Published online 6 March 2005
  doi10.1038/nn1421
• Gaze fixation and the neural circuitry of face
  processing in autism

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Two-year-olds with autism orient to
non-socialcontingencies rather than biological
motion

• Ami Klin, David J. Lin, Phillip Gorrindo, Gordon
  Ramsay Warren Jones
• Nature Vol 459 14 May 2009
• Video demonstration

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Two-year-olds with autism show no preferential
attention to biological motion, whereas control
children show significant preferences.
A Klin et al. Nature 000, 1-5 (2009)
doi10.1038/nature07868
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When the animation contains a physical
contingency, two-year-olds with autism do show
significant viewing preferences.
A Klin et al. Nature 000, 1-5 (2009)
doi10.1038/nature07868
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Conclusions

• Autism is genetic new research will point to
• What each of the genes does
• What causes the genes to be expressed
  (epigenetics eg. environmental factors)
• In general the genes affect brain development of
• Prefrontal lobe functions TOM and Mirror neuron
  system
• Perceptual functions related to preferences for
  human faces, biological motion and human vocal
  intonation

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What can we do?

• Right now the research evidence points to
  promising new areas for intervention
• perceptual training and the mirror neuron system
  in young children
• Interactive play
• Imitation
• mentalizing and other prefrontal lobe functions
  as the children mature
• TOM
• Working memory