Endophenotypes of autism spectrum disorder

So you can diagnose an autism spectrum disorder. But is that enough? Possible endophenotypes of autism spectrum
Digby Tantam

Proposed DSM-V criteria for ASD
Must meet criteria A, B, C, and D:

A. Persistent deficits in social communication and social interaction across contexts, not accounted for by general developmental delays, and manifest by all 3 of the following:
1. Deficits in social-emotional reciprocity; ranging from abnormal social approach and failure of normal back and forth conversation through reduced sharing of interests, emotions, and affect and response to total lack of initiation of social interaction,
2. Deficits in nonverbal communicative behaviors used for social interaction; ranging from poorly integrated- verbal and nonverbal communication, through abnormalities in eye contact and body-language, or deficits in understanding and use of nonverbal communication, to total lack of facial expression or gestures.
3. Deficits in developing and maintaining relationships, appropriate to developmental level (beyond those with caregivers); ranging from difficulties adjusting behavior to suit different social contexts through difficulties in sharing imaginative play and in making friends to an apparent absence of interest in people


1. Social-emotional reciprocity (mechanics of social interaction)
2. Nonverbal communication
3. Developing and maintaining relationships


Nonverbal impairment
Deficits in social-emotional reciprocity (‘rules’ of social interaction) 
Possible impairment in social relationship formation

What changes from DSM-IV
Merging of AS with ASD and disintegrative disorder
Lamented by Aspies
Disintegrative disorder is progressive
Disappearance of Rett syndrome
Probably heralds separation of syndrome and aetiology, which is welcome
Possible increase in age criterion
May raise later confusion with schizophrenia (again)
Disappearance of the triad
Lamented by Wing, Gould, and Gillberg(Research Autism paper) because of Falck-Ytter
who argue that social interaction and
But still mixing primary impaired in social interaction with its effects in social relationship
Verbal communication disappears
Some Aspies think it reduces possible of Autism Spectrum Condition

Falck-Ytter at al

Scanpaths complex: mouths not always chosen over eyes, other factors e.g. eye aversion, need to disambiguate language


Nonverbal impairment modulated by anxiety?
Deficits in social-emotional reciprocity (‘rules’ of social interaction)  modulated by context?
Possible impairment in social relationship formation

Proposed DSM-V criteria for ASD (cont)

B. 1. Stereotyped or repetitive speech, motor movements, or use of objects; (such as simple motor stereotypies, echolalia, repetitive use of objects, or idiosyncratic phrases).
2. Excessive adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change; (such as motoric rituals, insistence on same route or food, repetitive questioning or extreme distress at small changes).
3. Highly restricted, fixated interests that are abnormal in intensity or focus; (such as strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests).
4. Hyper-or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment; (such as apparent indifference to pain/heat/cold, adverse response to specific sounds or textures, excessive smelling or touching of objects, fascination with lights or spinning objects).
C. Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited capacities)
D. Symptoms together limit and impair everyday functioning.

Proposed DSM-V criteria for ASD (cont)

B.
Stereotypies No more common than in ID.
Link with social isolation. Dopamine mediated. Non-specific?
Routines, rituals
OCD, Most common absence in PDD-NOS. Anxiety-related
Special interests
Attention, but also with satisfaction, and cognitive phenotype Linked with clumsiness
Hyper-or hypo-reactivity to sensory input
Identity ? But may be absent
C. Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited capacities)
D. Symptoms together limit and impair everyday functioning.

Major remaining problem
Heterogeneous syndrome
Geared to categorical diagnosis (good for services) but not to dimensional approach
Dimensions, cognitive phenotypes, are more useful for advice and remediation
Dimensions, endophenotypes, are likely to be more important in genetic studies

“Here, we report that quantitative trait analyses of ASD symptoms combined with case-control association analyses using distinct ASD subphenotypes identified on the basis of symptomatic profiles result in the identification of highly significant associations with 18 novel single nucleotide polymorphisms (SNPs). The symptom categories included deficits in language usage, non-verbal communication, social development, and play skills, as well as insistence on sameness or ritualistic behaviors”
Hu, V. W., Addington, A., & Hyman, A. (2011). Novel autism subtype-dependent genetic variants are revealed by quantitative trait and subphenotype association analyses of published GWAS data. PLoS ONE, 6(4), e19067.

“We present evidence from our own twin studies, and review relevant literature on autism and autistic-like traits in other groups. We suggest that largely independent genes may operate on social skills/impairments, communication abilities, and RRBIs, requiring a change in molecular-genetic research approaches”.
Happe, F., & Ronald, A. (2008). The 'Fractionable Autism Triad': A Review of Evidence from Behavioural, Genetic, Cognitive and Neural Research. [Article]. Neuropsychology Review, 18(4), 287-304.

Gaze following and the interbrain

Project Development

Tantam, Cordess, HolmesTotal amount of gazing, controls=people with ASBut gaze plus some other happening on the face of another person was different

Tantam, D. Characterizing the fundamental social handicap in autism. ActaPaedopsychiatrica, 55, 83-91, 1991
Gaze reflex 1
Focus on eyes (but means suppression of agonistic response)
Gaze reflex 2
Follow other’s gaze to its destination

All tool users that understand words and signs

Tantam, D. Characterizing the fundamental social handicap in autism. ActaPaedopsychiatrica, 55, 83-91, 1991
Gaze reflex 1
Focus on eyes (but means suppression of agonistic response)
Gaze reflex 2
Follow other’s gaze to its destination
Gaze reflex 3
Follow direction of other’s gaze back to their eyes to detect their expression

Brain regions showing positive change in coupling with the right pSTS (red to yellow) and FG (blue to turquoise) while viewing gaze shifts versus opening/closing the eyes.
Nummenmaa L et al. Cereb. Cortex 2010;20:1780-1787
© The Authors 2009. Published by Oxford University Press.

CONCLUSIONS: This study provides preliminary evidence of impaired neural connectivity in the corpus callosum/cingulum and temporal lobes involving the inferior longitudinal fasciculus/inferior fronto-occipital fasciculus and superior longitudinal fasciculus in ASDs. These findings provide preliminary support for aberrant neural connectivity between the amygdala, fusiform face area, and superior temporal sulcus-temporal lobe structures critical for normal social perception and cognition.
Jou, R. J., Jackowski, A. P., Papademetris, X., Rajeevan, N., Staib, L. H., & Volkmar, F. R. (2010). Diffusion tensor imaging in autism spectrum disorders: preliminary evidence of abnormal neural connectivity. Australian And New Zealand Journal Of Psychiatry, 45(2), 153-162

Chiu, P. H., Kayali, M. A., Kishida, K. T., Tomlin, D., Klinger, L. G., Klinger, M. R., et al. (2008). Self responses
along cingulate cortex reveal quantitative neural phenotype for high-functioning autism. Neuron, 57(3), 463-473.

“Attributing behavioral outcomes correctly to oneself or to other agents is essential for all productive social exchange. We approach this issue in high-functioning males with autism spectrum disorder (ASD) using two separate fMRI paradigms. First, using a visual imagery task, we extract a basis set for responses along the cingulate cortex of control subjects that reveals an agent-specific eigenvector (self eigenmode) associated with imagining oneself executing a specific motor act. Second, we show that the same self eigenmode arises during one's own decision (the self phase) in an interpersonal exchange game (iterated trust game).
Third, using this exchange game, we show that ASD males exhibit a severely diminished cingulate self response when playing the game with a human partner. This diminishment covaries parametrically with their behaviorally assessed symptom severity, suggesting its value as an objective endophenotype.
These findings may provide a quantitative assessment tool for high-functioning ASD.”
Chiu et al, 2008

Gaze reflex 1 and 2 provide training in where to look and facilitate focussed social development

People with AS lack gaze reflex 1 or at least look at geometric shapes preferentially (Pierce) do not attribute animation to shapes, do not treat machines as people

Schippers, M. B., Roebroeck, A., Renken, R., Nanetti, L., & Keysers, C. (2010). Mapping the information flow from one brain to another during gestural communication. Proceedings of the National Academy of Sciences, -.

Learning to look directly at right things (2)

Learning to look at the right things
But this may represent requirement to disambiguate language: mouth looking is more common in some children and some cultures
Mouth looking may be more common in people with SLI, and not in people with ASD

The Wright brothers
Synchrony
Armies, churches, organizations, and communities often engage in activities for example, marching, singing, and dancing that lead group members to act in synchrony with each other.….Across three experiments,
people acting in synchrony with others cooperated more in subsequent group economic exercises, even in situations requiring personal sacrifice. Our results also showed that positive emotions need not be generated for synchrony to foster cooperation. In total, the results suggest that acting in synchrony with others can increase cooperation by strengthening social attachment among group members
Wiltermuth and Heath, 2009, Psychological Science

Mirror neuron studies

I am looking at what you are looking at, and we both know that
Each of us is paying attention to it.
So we have the same things on our mind:
Our mental contents are shared

How do we know who has high social status?
Pride
They attract looks

Not something I have to think about, or send a particular
Message. So unlike speaking: more like just being connected
‘The interbrain’

An idea whose time has come?

Palinkas, LA, Suedfeld, P Psychological effects of polar expeditions. Lancet 2008; 371: 153-63.

Who is Jake? Look him up in the brain index: the cache of all the information about experiences with Jake

Superior temporal cortex and PFC network in gaze shifting: Nummanmaa et al

Figure 2.
Brain regions showing positive change in coupling with the right pSTS (red to yellow) and FG (blue to turquoise) while viewing gaze shifts versus opening/closing the eyes. Areas that showed a change in coupling with both FG and pSTS are shown in green. Mean coordinates of the pSTS and FG source regions used in the connectivity analyses are shown as red and blue spheres, respectively. Maps are thresholdedatP < 0.005, unc. for visual inspection, and the color bars denote the Tstatistic range. FEF, frontal eye field; FG, fusiform gyrus; IPS, intraparietal sulcus; MFG, middle frontal gyrus; SMG, supramarginal gyrus; STG, superior temporal gyrus; pSTS, superior temporal sulcus.

Looking at the right things
Inferring things from other’s gaze direction

Falling prevalence of ASD in boys and men based on community survey of Sheffield city (pop. 400 000) N=124

Falling prevalence of ASD in boys and men based on community survey of Sheffield city (pop. 400 000) N=124
Secondary peak of fathers?


Exposure to social situation? Mimicry? Evidence of drama?
ABA? Esp gaze direction
Teach people to look
Teach people to control odd behaviour

Dealing with anxiety
Dealing with transitions
Social value of special interests

Stereotypies are an indication of intellectual disability, as is the poverty or complexity of interests

Endophenotypes within non-verbal impairment
With dyspraxia (is this the nonverbal element?)
VIQ>PIQ
‘Typical’ Asperger syndrome
More ‘temporal’
With impaired narrative ability and possibly other SLI (is this the social interaction element)
PIQ>VIQ
‘Atypical AS’ or PDD-NOS
More ‘frontal’
Association with ADHD

Typical Asperger syndrome: NV expressive impairment
Unusual manner, gives immediate impression of idiosyncrasy due to impaired nonverbal expressiveness
Makes contact on own terms
May discuss unusual or particular interests
Problems with unexpected or unclear situations
19/08/2011

Atttention direction

Associations with ‘typical’ ASD
Clumsiness
Topographical disorientation
Unusual deployment of attention on environment: seeing the trees, not the word
Sociolinguistic impairment: concrete language, failure to understand some humour (puns OK)
Catastrophic reaction to social demand, e.g. conflict, loud noise, change
Problems in making friends

Treatment methods for typical ASD
ABA and other methods of capturing engagement may work in children
Remedial gymnastics has effect on social difficulties?
Mimicry (but not imitation) e.g drama therapy

Atypical Asperger syndrome: a new clinical syndrome and linked to impaired social interaction?
Primary abnormality is impaired social interpretation
May be conspicuous lack of a theory of mind
Lack of internal narrative
Ability to make relationships but not to keep them
May be behavioural problems (‘pathological demand avoidance’)
Lack of persuasiveness and ‘social influencing power’

The language of the eyes
Who is being shot?
Terrorists or partisans?

Empathy disorders
Psychopathy in which there may be:
An impairment of response to threat expressions
A turning off of normal empathic responsiveness
Autistic spectrum disorders
An impairment in the response to all nonverbal expression, with a consequent reduction in emotional responsiveness

Cognitive and affective empathy
Fifty-two boys (25 aggressive and 27 non-aggressive) were compared for levels of aggression and for cognitive and affective empathy as expressed during a group interview involving bibliotherapy.
Aggressive boys showed half the level of affective empathy as non-aggressive boys, although the groups did not differ in cognitive empathy
Study of cognitive and affective empathy in aggressive boys(Schechtman, Z. (2002) Cognitive and affective empathy in aggressive boys: implications for counselling. International Journal for the Advancement of Counselling, 24, 211-.
Although both groups can appear uncaring, our findings suggest that the affective/information processing correlates of psychopathic tendencies and ASD are quite different. Psychopathic tendencies are associated with difficulties in resonating with other people’s distress, whereas ASD is characterised by difficulties in knowing what other people think
JONES, A. P., HAPPÉ, F. G. E., GILBERT, F., BURNETT, S. & VIDING, E. 2010. Feeling, caring, knowing: different types of empathy deficit in boys with psychopathic tendencies and autism spectrum disorder. Journal of Child Psychology and Psychiatry, 51, 1188-1197
4 July 07
10th. European Congress of Psychology

Aggression and empathy
Increased perspective taking reduces aggression
(Richardson et al, 1994,Empathy as a cognitive inhibitor of interpersonal aggression. Aggressive Behaviour, 20, 276-289)
Secondary inhibition (Feshbach and Feshbach, 1969) results from seeing the fear (Blair) or disgust (Nichol) in the other and acts to mitigate aggression
(de Paul et al, 2006, Aggression inhibition in high- and low-risk subjects for child physical abuse: effects of a child’s hostile intent and the presence of mitigating information, Aggressive Behaviour, 32, 216-230
Actress Janet Leigh from the shower scene in Hitchcock's Psycho

Narrative coherence
Inability to hold up against persuasion:
A lack of an internal narrative “I could have done that”
Acceptance of strongest narrative, or authority’s narrative, of most recently repeated narrative
Link with theory of mind
Bright-Paul, A., C. Jarrold, et al. (2008).
Autobiographical memory
Bruck, M., K. London, et al. (2007)
www.existentialacademy.com
61

Coping with a lack of identity
Fads
‘Obsessive’ relationships
Lack of identity in many people with ASD
Adopting identity wholesale
Joining charismatic groups
Moving places and work
Searching for identity
‘Transexualism’
‘Aspie’
Identities off the peg
Gangster
Professor
Teddy bear
2 Nov 2010
Seeing the light – or ticking the box?

Other endophenotypes that may be more common in atypical ASD
Dyslexia
Speech and language impairment, with reduced understanding of speech
Dysexecutive syndrome
The consequence of ADHD?

bb

Treating dysexecutive syndrome
Self-care
Mentoring
Methylphenidate
Diaries/ organizers

A particularly wide ranging tool kit
Readiness to consider the most intense emotional issues and in the next moment, the most practical and cognitive ones
Having a clear grasp of the individual in front of you, not just in life experience, or temperament, but in cognitive abilities
Be aware of shame and shaming
The limitless potential of social control by shaming

Contributors
Sheffield survey
Myles Balfe
Ting Chen
Mike Campbell
submitted to Autism
Bullying project
Paul Naylor
Jenny Wainscot
Jenna Williams
15 medical students
International Journal of Psychology
Parents, teachers, and people with Asperger syndrome
Sheffield Asperger Parents Action Group

Consequences of bullying
Passive failure to be included
Reduced use of community resources (social exclusion)
Experience of being unwanted/marginalized
Active rejection , blaming, scapegoating
Stigma as a means of keeping threatening Other at a distance
Bullying
Painted Bird by Edward Gafford, inspired by the novel ‘Painted Bird’ by JerzyKosiński, itself based on what has been claimed is a fictive war-time experience of the author in Poland

Does social exclusion lead to functional movement impairment
Is there a difference in the amount of physical activity of pupils with AS compared to others?
Mean number of steps per hour: AS group = 902, control group = 1312 (t= -2.645, p = .027)

Where were people with AS in Sheffield?
Most living at home, even above 30.
Most had difficulties coping with changes in everyday environments
Difficulties moving between places (for example using public transport)
Most common places frequented were libraries and cinemas

Bullied pupils and those with SEN report feeling unhappier and have less commitment to school than pupils who are not bullied and have no SEN.
For pupils with SEN or no identified SEN, the risk of being bullied declines by approximately 9 per cent each chronological year.
Pupils bullied in Year 9 (13-14-year-olds) are much more likely to drop out of school at Year 11 (15-16-year-olds) than those who were not bullied. This trend is even more pronounced for pupils with SEN.
Prevalence of bullying in secondary school by SEN type: Analysis of combined NPD and LSYPE data files. Naylor, P., Dawson, J., Emerson, E., and Tantam, D. (2011) N=15 770 13-14 year olds in mainstream school

Factors that might influence empathy suppression by people with AS
Lack of emotional empathy
Neurotypicals are united, and do not deserve empathy
Uproar
Lack of a shared social contract: ‘dissociation’
Lack of social influencing power

Abuse
How many people with ASD have been abused?
Difficult to establish but possibly a significant no.
Suspicion should be raised by deterioration in behaviour, sexual disinhibition, regression
Interviewing may be unreliable as people with ASD may not have a clear cut conception of abuse or even of sexually inappropriate behaviour
People with ASD may feel that sexual favours are a fair exchange for social contact
Need institutional policies for monitoring
Friday, 19 August 2011
Lunch-time meeting, Brandon Unit, Leicester

Relationships
Not being attractive (more often in heterosexual men)
Being empathic
Being too compliant (more often in women or some homosexual men)
Not being able to sustain relationship
Knowing what someone wants without them saying
Anxiety about failing in relationships
May find images or masturbation more attractive than actual people
Unreciprocated attraction
Stalking
Sexual threatening behaviour
Inappropriate sexual touching
May flip into aggression towards sexually attractive others
Abusive/ inappropriate/intimidating relationships
Coercive sexuality

Medication for psychiatric disorder
Changing circumstances esp power and influence
Post aggression feedback
Identification of mounting tension
Prevention of reinforcement

Dealing with lack of empathy
Prevention of exploitation
Modelling
Empathy training?

Telling the truth vs. knowing the truth
Narrative

Medicolegal problems
Out of sight out of mind
Modifications to counselling
‘Alexithymia’

Emotional problems in adolescents and adults with Asperger syndrome(findings from Sheffield survey)
Self-harm: thoughts 50%, actual 11%
Violence: threats 83%, actual 34%
Bullied 90%, 30% currently (includes adults)
Majority have anxiety-related disorder

Empathy disorders
Psychopathy in which there may be:
An impairment of response to threat expressions
A turning off of normal empathic responsiveness
Autistic spectrum disorders
An impairment in the response to all nonverbal expression, with a consequent reduction in emotional responsiveness
4 July 07

FromAutism spectrum disorders: a life-span perspectiveJessica Kingsley2011

Aggression and empathy
Increased perspective taking reduces aggression
(Richardson et al, 1994,Empathy as a cognitive inhibitor of interpersonal aggression. Aggressive Behaviour, 20, 276-289)
Secondary inhibition (Feshbach and Feshbach, 1969) results from seeing the fear (Blair) or disgust (Nichol) in the other and acts to mitigate aggression
(de Paul et al, 2006, Aggression inhibition in high- and low-risk subjects for child physical abuse: effects of a child’s hostile intent and the presence of mitigating information, Aggressive Behaviour, 32, 216-230
Actress Janet Leigh from the shower scene in Hitchcock's Psycho

Cognitive and affective empathy
Fifty-two boys (25 aggressive and 27 non-aggressive) were compared for levels of aggression and for cognitive and affective empathy as expressed during a group interview involving bibliotherapy.
Aggressive boys showed half the level of affective empathy as non-aggressive boys, although the groups did not differ in cognitive empathy
Study of cognitive and affective empathy in aggressive boys(Schechtman, Z. (2002) Cognitive and affective empathy in aggressive boys: implications for counselling. International Journal for the Advancement of Counselling, 24, 211-.
Although both groups can appear uncaring, our findings suggest that the affective/information processing correlates of psychopathic tendencies and ASD are quite different. Psychopathic tendencies are associated with difficulties in resonating with other people’s distress, whereas ASD is characterised by difficulties in knowing what other people think
JONES, A. P., HAPPÉ, F. G. E., GILBERT, F., BURNETT, S. & VIDING, E. 2010. Feeling, caring, knowing: different types of empathy deficit in boys with psychopathic tendencies and autism spectrum disorder. Journal of Child Psychology and Psychiatry, 51, 1188-1197

Does empathy lead to violence, either through an increase in aggression or a reduction in violence inhibition?
Correlational studies link low empathy and increased aggression
Empathy ‘mitigates aggression’ (Bjorkqvist, Osterman, & Kaukiainen, 2000)
But aggressive two year-olds may actually show more empathy than non-aggressive two years olds (Gill & Calkins, 2003)
Distinction between affective and cognitive empathy?
4 July 07

Reported prevalence of psychiatric disorder in older adolescents and adults

Indicators of violent reoffending: the new OASys Violence PredictorPhilip Howard, Senior Research OfficerJackie Seaton, Senior Probation OfficeOffender Assessment and Management UnitNOMS, Ministry of Justice for England and Wales
Sections 1-12
1: offending information [criminal history]
2: [current] offence analysis
3: accommodation
4: education, training and employability
5: financial management and income
6: relationships
7: lifestyle and associates
8: drug misuse
9: alcohol misuse

What motivates aggression in AS?
Doing the right thing
Being accepted, perhaps in a deviant group
Utilization behaviour
Effort at communication
Catastrophic reaction
Asserting dominance
Modelling
Tension relief
Hypomania, depression
"This is my son” 4 year old artist from Art Gallery on OASIS home page

Reported prevalence of psychiatric disorder in older adolescents and adults

Psychological disorders associated with AS(many of these disorders probably greater in more able group)
2 ‘Attachment disorder’ (disorganized in ADHD)
7 Polymorphous anxiety: encopresis, checking, sleep disturbance, ‘shyness’
11-13 Surge of anxiety-related problems including OCD, dysmorphophobia, panic disorder
16-18 Secondary depression, social phobia
>16
Progressive social withdrawal often attributed to schizophrenia
Late adolescence bipolar disorder
Brief ‘cycloid’ psychoses
Non-psychotic hallucinoses
>18 ‘Catatonia’
>25 Paranoid states
>35 Social withdrawal, isolation, relationship disrepair

Treating anxiety disorder
Recognition
SSRIs
Counselling (no particular advantage to CBT)
Prevention

Grief
May be absent or delayed
May be more for places or times than people
Grieving over lost childhood is common
Reflected in interests
In wanting to be with younger people
Ruminations
Ruminations also serve to put past right
Lack of emotional as opposed to cognitive coping

Owen Thor Walker
Home schooled from aged 13 because of bullying, provided code to cyber crime syndicate that took £10.3M from private bank accounts (he got £15,500 in payment for botnet code).
New Zealand judge did not impose a custodial sentence because of the effect on his career, but fined him £5000.
Subsequently hired by TelstraClear, a telecomms company, to act as security consultant

Further information
Due out 2011

That’s as far as we go, folks
So, thanks for listening

Endophenotypes of autism spectrum disorder

by Dilemma consultancy on Aug 20, 2011

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Endophenotypes of autism spectrum disorder — Presentation Transcript