the riddle of autism – solved!

Neurologically SpeakingPart 3

Martha S. Burns, Ph.D.

September 2009

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

Abrahams and Geschwind (2008)Advances in autism genetics: on the

threshold 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

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

Structural Architecture of the Human Cortex pre-natal to 16 years

So what does this part of the brain do?

Pre-frontal Lobes

• Ventromedial – connected to limbic system– Important in delayed gratification– Empathy

• Dorsolateral – – Organization, planning, flexibility– Working memory– Processing speed

Meeting of minds: the medial frontal cortex and social cognition.

Amodio, DM and Frith, CD. (2006) Nature Reviews Neuroscience 7,

268-277.

Amodio et al. Nature Reviews Neuroscience 7, 268–277 (April 2006) | doi:10.1038/nrn1884

Amodio et al. Nature Reviews Neuroscience 7, 268–277 (April 2006) | doi:10.1038/nrn1884

Mindblind Eyes: An Absence ofSpontaneous Theory of Mind in

Asperger Syndrome• Atsushi Senju,Victoria Southgate, Sarah

White, Uta Frith

• SCIENCE VOL 325 14 AUGUST 2009

.

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 Sally’s 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 Sally’s 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

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

Limbic System

• Channeling emotion and motivation – To behaviorally relevant motor acts, mental

content and extrapersonal event– Is accomplished through the paralimbic

regions

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 wereilluminated and chimesounded, and (C) an actor reached through the window above the box in which the ball was placed and retrievedthe ball. The participants were familiarized to the contingency between (B) and (C).In (D), the puppet moves the ball while the actor is lookingaway. This operation induces a false belief in the actor about the location of the ball.

Published by AAAS

A. Senju et al., Science 325, 883 -885 (2009)

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 < 0.05; **P < 0.01. Dotted lines indicate chance level. Statistical test used: (A), t test; (B), binominal

test.

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 someone’s preference.

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

Emotional circuits

Tuning the developing brainto social signals of emotions

• Jukka M. Leppänen and Charles A. Nelson

• NRNS 1.09

b | Results showing that discrimination of emotionalexpressions in bimodal (audiovisual) stimuli emerges earlier than discrimination ofemotional expressions in unimodal auditory or visual stimuli. c | After habituation tohappy expressions on different faces, 7-month-old infants could discriminate thisexpression from fearful and angry expressions when the stimuli were presented uprightbut not when they were inverted

Emotion-related neuralsystems (the amygdala and the orbitofrontal cortex(OFC)) receive visual information from cortical regionsthat are involved in the visual analysis of invariant andchangeable aspects of faces (face-sensitive regions in thefusiform gyrus and the posterior superior temporal sulcus(pSTS)).

Giacomo Rizzolatti, Maddalena Fabbri-Destro and Luigi Cattaneo

Mirror 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

Giacomo Rizzolatti, Maddalena Fabbri-Destro and Luigi Cattaneo

Mirror 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

Iacoboni and Dapretto Redgrave Nature Reviews Neuroscience 7, 942–951 (December 2006) | doi:10.1038/ nrn2024

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

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

Methods

• 12 children diagnosed with an Autism Spectrum Disorder– 6 trained, 6 control – Age matched (Trained=9.17±1.47 years; Control= 9.0±1.47

years, n.s.)

• Brainstem neurophysiology tests– /da/ in quiet and background noise– rising and falling /ya/ in quiet

Pitch tracking and phase locking of F0 improved

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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; | doi:10.1038/nn1421

• Gaze fixation and the neural circuitry of face processing in autism

Figure 1. Study designs and exemplar stimuli.(a) Study I: 2 (Emotion) 2 (Orientation) repeated-measures design. Twenty-four emotional faces and 16 neutral faces were used, half with eyes and face oriented straight ahead, and half with face and eyes averted 45 degrees (equal toward the right and left). (b) Study II: examples of matched familiar versus unfamiliar photographs. Photographs of participants' family and friends were matched for gender, age, facial expression and orientation as closely as possible to photographs taken by other study participants.

Two-year-olds with autism orient to non-social

contingencies rather than biological motion• Ami Klin, David J. Lin, Phillip Gorrindo,

Gordon Ramsay & Warren Jones

• Nature Vol 459| 14 May 2009

• Video demonstration

A Klin et al. Nature 000, 1-5 (2009) doi:10.1038/nature07868

Two-year-olds with autism show no preferential attention tobiological motion, whereas control children show significant preferences.

A Klin et al. Nature 000, 1-5 (2009) doi:10.1038/nature07868

When the animation contains a physical contingency, two-year-olds with autism do show significant viewing preferences.

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

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