Neurobiology of autism

Neurobiology of autism
By:Christopher Gillberg, MD, PhD
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)
* 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
* 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
* Tuberous sclerosis
o 3-9% of all autism cases, more common in those with epilepsy
o chromosome 16p involved in one variant (autism susceptibility genetic area? ADHD susceptibility genetic area)
o dopamine genes on chromosome 9 affected in other TS variant
o autism likely if TS lesions in temporofrontal regions and if there are many lesions

* Herpes encephalitis
o affects temporofrontal areas more often than other brain structures
o can lead to classic symptoms of autism even in previously unaffected individuals who are 14 and 31 years of age
* Thalidomide embryopathy
o 5% of all have (classic) autism
o Brainstem lesions
o 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
* 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
* 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)

* Neuroligin genes on X-chromosome mutated in some cases
o (Jamain, Bourgeron, Gillberg et al 2003. Laumonnier et al 2004)
* Neuroligin genes on other chromosomes, including chromosome 17
o (Jamain et al 2003)
* Other neurodevelopmental genes according to microarray study
o (Larsson, Dahl, Gillberg et al 2003)

Where in the brain is autism?

* Clinical finding: macrocephalus common
o (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
o (Gillberg & Coleman 2000)
* Autopsy data suggest: amygdala, pons and cerebellum
o (Bauman 1988)
* Brainstem damage suggested by
o Thalidomide
+ (Strömland, Gillberg et al 1994)
o Moebius syndrome association
+ (Gillberg & Steffenburg 1997)
o CHARGE association
+ Johansson et al 2004
o Auditory brainstem responses
+ (Rosenhall, Gillberg et al 2003)
o Decrease in/lack of postrotatory nystagmus
+ (Ornitz, Ritvo 1967)
o Aberrant muscle tone and concomitant squint
+ (Gillberg & Coleman 2000)
* Cerebellar dysfunction suggested by
o Autopsy studies
+ (Bauman et al 1992, Bayley et al 1999, Oldfors, Gillberg et al 2000, Weidenheim, Rapin, Gillberg et al 2001)
o Imaging studies
+ (Courchesne 1988)
o Relationship to ataxia
+ (Åhsgren, Gillberg et al 2003)
* Frontotemporal brain dysfunction suggested by
o Autopsy studies
o Functional imaging studies
o Neuropsychological studies
o Combined neuropsychological-neuroimaging studies
o Clinical picture
* Neuropsychological studies show
o Metarepresentation problems
o Central coherence problems
o Non-verbal learning disability in AS
o Verbal learning disability in AD
o Executive function deficits
o Procedural (complex) learning deficits
o Superior fact learning
o Aberrant reading of facial expression

* At least four biological variants of autism?
o Early brainstem/cerebellar associated with severe secondary problems
o Midtrimester bitemporal lobe damage
o Uni- or bilateral frontotemporal dysfunction in high-functioning cases
o Multi-damage 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

Where in the brain is autism?
* Dopamine
o (Gillberg et al 1987)
* Serotonin (in LD also)
o (Coleman 1976)
* Noradrenaline dysfunction
o (Gillberg et al 1987)
* Neuroligins
o (Jamain et al 2003)
* GFA-protein
o (Ahlsén et al 1993)
* Gangliosides
o (Nordin et al 1998)
* Endorphines
o (Gillberg et al 1985)
* Immune system
o (Plioplys 1989)
* Glycine, GABA, Ach, glutamate?

Psychopharmacology of autism
* Only dopamine antagonists (neuroleptics) have been convincingly shown to affect core symptoms of autism
o (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?
* 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
* 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
* No medication for majority
* Atypical neuroleptics, antiepileptics, SSRIs, stimulants, lithium (and other drugs) for some
* Diets??
* Physical exercise!!
* “Sensory awareness” environment (reduce noise, certain sounds, smell etc.)
* Concrete, visual (not always), straight-forward
* Minimize ambiguities and symbolic interpretation

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)

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


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!

Neurobiology of autism .ppt