Neurobiology of autism

 Christopher Gillberg, MD, PhD

• Cardiff May 2004

Christopher Gillberg
 Professor of Child and Adolescent
Psychiatry
 University of Göteborg (Queen Silvia´s
Hospital)
 University of London (St George´s
Hospital Medical School)
Autism spectrum disorders:
neurobiology
 Overview
 Acquired brain lesions
 Genetics
 Where in the brain is autism?
 Psychosocial interactions
 Intervention implications
 Outcome implications
 The future
Overview
 At least four clinical presentations of autism
(autism/autistic spectrum disorder)
 Autistic disorder (Kanner syndrome)
 Asperger’s disorder (Asperger syndrome)
 Childhood disintegrative disorder (Heller
syndrome)
 PDD NOS (atypical autism, other autistic-like
condition, other autism spectrum disorder)
Overview
 Prevalence much higher than believed in the past:
ASD in 1% of population, AD in 0.2%
 Associated with learning disability 15% (80% in
autistic disorder/AD)
 Associated with epilepsy 5-10% (35% in AD)
 Medical disorder in 5% (25% in AD)
 Skewed male:female ratio 2-4:1
 High rate of visual, hearing and motor impairments
(including at birth)
 Sibling rate raised; identical twin conocordance rate
much raised in classic autism
”Acquired” brain lesions
 Tuberous sclerosis, Fragile X syndrome, Partial
tetrasomy 15, Down syndrome, XYY, XO,
Hypomelanosis of Ito, Rett complex variants,
Angelman syndrome, Williams syndrome,
CHARGE association, Smith-Magenis
syndrome, Smith-Lemli-Opitz syndrome, 22q11
deletion, Silver-Russell syndrome, Fetal alcohol
syndrome, Retinopathy of prematurity,
Thalidomide embryopathy, Moebius
syndrome, Herpes and rubella infection
”Acquired” brain lesions
 Known medical disorders 25% in autistic
disorder ”proper” (unselected samples) and
2-5% in Asperger syndrome
 These are either genetic in their own right,
affect autism susceptibility gene areas, or
cause brain lesions through direct/indirect
insults
 High rate of pre- and perinatal risk factors
”Acquired” brain lesions
 Tuberous sclerosis
– 3-9% of all autism cases, more common in
those with epilepsy
– chromosome 16p involved in one variant
(autism susceptibility genetic area? ADHD
susceptibility genetic area)
– dopamine genes on chromosome 9 affected in
other TS variant
– autism likely if TS lesions in temporofrontal
regions and if there are many lesions
Acquired brain lesions
 Herpes encephalitis
– affects temporofrontal areas more often
than other brain structures
– can lead to classic symptoms of autism
even in previously unaffected individuals
who are 14 and 31 years of age
Acquired brain lesions
 Thalidomide embryopathy
– 5% of all have (classic) autism
– Brainstem lesions
– Day 20-24 postconceptionally
Genetics
 Sibs affected in 3%: core syndrome
 Sibs affected in 10-20%: spectrum disorder
 Identical twins affected in 60-90%
 Non-identical twins affected in 0-3%
 All of these findings refer to probands with
autism proper, not spectrum disorders
Genetics
 First-degree relatives increased rates of
affective disorders (depression, bipolar),
social phobia, obsessive-compulsive
phenomena, and ”broader phenotype
symptoms”, ADHD?, Tourette syndrome?
 First-degree relatives also show possibly
increased rates of learning disorders
including MR, dyslexia and SLI
Genetics
 Genes on certain chromosomes (e.g. 2,
6, 7, 16, 18, 22, and X) may be important
(genome scan studies of sib-pairs)
 Clinical findings in particular
syndromes such as partial tetrasomy 15
(15q), Angelman (15q), tuberous
sclerosis (9q, 16p), fragile X (X), Rett
syndrome (X), Turner syndrome (X)
Genetics
 Neuroligin genes on X-chromosome mutated
in some cases
– (Jamain, Bourgeron, Gillberg et al 2003. Laumonnier et al
2004)
 Neuroligin genes on other chromosomes,
including chromosome 17
– (Jamain et al 2003)
 Other neurodevelopmental genes according
to microarray study
– (Larsson, Dahl, Gillberg et al 2003)
Where in the brain is autism?
 Clinical finding: macrocephalus common
– (Bayley et al 1997, Gillberg & deSouza 2002)
 Acquired brain lesions implicate temporal,
frontal, fronto-temporal and bilateral
dysfunction in core syndrome; right or left
dysfunction in spectrum disorder
– (Gillberg & Coleman 2000)
 Autopsy data suggest: amygdala, pons and
cerebellum
– (Bauman 1988)
Where in the brain is autism?
 Brainstem damage suggested by
– Thalidomide
• (Strömland, Gillberg et al 1994)
– Moebius syndrome association
• (Gillberg & Steffenburg 1997)
– CHARGE association
• Johansson et al 2004
– Auditory brainstem responses
• (Rosenhall, Gillberg et al 2003)
– Decrease in/lack of postrotatory nystagmus
• (Ornitz, Ritvo 1967)
– Aberrant muscle tone and concomitant squint
• (Gillberg & Coleman 2000)
Where in the brain is autism?
 Cerebellar dysfunction suggested by
– Autopsy studies
• (Bauman et al 1992, Bayley et al 1999, Oldfors,
Gillberg et al 2000, Weidenheim, Rapin, Gillberg et
al 2001)
– Imaging studies
• (Courchesne 1988)
– Relationship to ataxia
• (Åhsgren, Gillberg et al 2003)
Where in the brain is autism?
 Frontotemporal brain dysfunction
suggested by
– Autopsy studies
– Functional imaging studies
– Neuropsychological studies
– Combined neuropsychological-
neuroimaging studies
– Clinical picture
Where in the brain is autism?
 Neuropsychological studies show
– Metarepresentation problems
– Central coherence problems
– Non-verbal learning disability in AS
– Verbal learning disability in AD
– Executive function deficits
– Procedural (complex) learning deficits
– Superior fact learning
– Aberrant reading of facial expression
Where in the brain is autism?
 At least four biological variants of
autism?
– Early brainstem/cerebellar associated with
severe secondary problems
– Midtrimester bitemporal lobe damage
– Uni- or bilateral frontotemporal
dysfunction in high-functioning cases
– Multi-damage autism
Where in the brain is autism?
 Likely that several functional neural
loops are implicated and that all
impinge on neurocognitive/social
cognitive functions that are crucially
(but possibly not specifically) impaired
in autism
– (Gillberg 1999, Gillberg & Coleman 2000)
Where in the brain is autism?
 Dopamine
– (Gillberg et al 1987)
 Serotonin (in LD also)
– (Coleman 1976)
 Noradrenaline dysfunction
– (Gillberg et al 1987)
 Neuroligins
– (Jamain et al 2003)
 GFA-protein
– (Ahlsén et al 1993)
 Gangliosides
– (Nordin et al 1998)
 Endorphines
– (Gillberg et al 1985)
 Immune system
– (Plioplys 1989)
 Glycine, GABA, Ach, glutamate?
Psychopharmacology of
autism
 Only dopamine antagonists
(neuroleptics) have been convincingly
shown to affect core symptoms of
autism
– (van Buitelaar 2000)
 SRIs?
 Antiepileptics??
 Peptides?? And peptide-targeted drugs
The pathogenetic chain
 Genetic or environmental insult
 Damage or neurochemical dysfunction
 Neurocognitive and social cognitive functions
restricted (metarepresentations, central coherence,
executive functions, procedural learning, )
 The ”syndrome” (or, sometimes, the ”arbitrary”
symptom constellation) of autism
 The dyad of social impairment plus the monad of
restricted behaviour pattern as a common
comorbidity? (rather than the triad?)
Psychosocial interactions
 Not associated with social class
 Not associated with psychosocial
disadvantage; however, “pseudoautism”
described in children exposed to extreme
psychosocial deprivation
 Temporally restricted major improvement in
good psychoeducational setting
 Immigration links? Indirect link with genetic
factors?
Psychosocial interactions
 Abnormal child triggers unusual
interactions
 Some parents have autism spectrum
disorders themselves
 Anxiety, violent behaviours, self-injury
and hyperactivity reduced in autism-
know-how-millieu
Implications for treatment
 All people are individuals first and foremost;
at least as true in autism as in
“neurotypicality”
 People WITH autism; not autistic people!
 Change attitudes
 Respect for people in the autism spectrum
 Focus on changing environment and
 Foster adaptive skills
Implications for treatment
 If known underlying disorder: treat this (and be
aware of syndrome-specific symptoms such as gaze avoidance in fragile X)

 If epilepsy: treat this (however, there are

major caveats here)
 If hearing, vision, or motor impaired: treat
this
 Psychoeducational measures
 Symptomatic biological treatments
• Gillberg & Coleman 2000
Implications for treatment
 No medication for majority
 Atypical neuroleptics, antiepileptics,
SSRIs, stimulants, lithium (and other
drugs) for some
 Diets??
• Gillberg & Coleman 2000
Implications for treatment
 Physical exercise!!
 “Sensory awareness” environment (reduce
noise, certain sounds, smell etc.)
 Concrete, visual (not always), straight-
forward
 Minimize ambiguities and symbolic
interpretation
• Gillberg & Peeters 2004
Outcome
 Very variable
 Better with early diagnosis
 Majority probably live to be old, but increased
mortality in subgroup
 Basic problems remain, albeit modified
 High rate of secondary psychiatric problems
(personality disorder, affective, social,
catatonia)
• Billstedt et al 2004, Howlin et al 2003, Nordin & Gillberg
1997
Outcome
 Better but also very restricted in Asperger
syndrome
• Cederlund et al 2004
 If autism and no language at age 7, classic
autism in adulthood
 If autism and no language at age 3, some
classic, some Asperger in adulthood
 If autism and some language at age 3,
most will be Asperger in adulthood
• Szatmari et al 2003
 The future
 Specific knowledge (including genetic) and
treatment for subgroups (new diagnostic
criteria)
 Symptomatic treatments
 Psychoeducation
 Acceptance and attitude change!
 People with autism, not autists or autistic
people! Cannot be stressed enough
 Respect!