Refrigerator mothers and beyond

The aetiology of autism

Neurobiology

Structural and functional abnormalities in the brain• At a certain point in post-natal development, autistic brains are larger, the

difference (10-20%) disappears with age.• Increased brain size in childhood is the most robust macroscopic feature of

autism, Increased cerebral grey and white matter and cerebellum increase occurring in the first 2-4 years. Certain portions of the brain, such as the amygdala, may be enlarged in autistic brains. Certain parts of the brain may function differently in autistic people. • "Minicolumns" in the brain may be formed differently and be more

numerous in autistic brains. • The entire brain may function differently in autistic people.

• Alteration of brain development soon after conception, significantly influenced by environmental factors. • An excess of neurons that causes local over connectivity in key brain regions. • Disturbed neuronal migration during early gestation.• Unbalanced excitatory–inhibitory networks.• Abnormal formation of synapses and dendritic spines, poorly regulated synthesis of synaptic protein, also associated with epilepsy.

Social brain

Underdeveloped areas of brain tend to be anterior parts….. Or what some refer to as the ‘social brain’.

Those with autism often have a number of difficulties socialising and socially interacting with others. Brothers (1990) identifies the following brain areas important in understanding 'the social brain' circuitry:

1 the amygdalae2 the orbitofrontal cortex & medial frontal cortex 3 the superior temporal gyrus & sulcus.

Areas of possible difficulty Functions

Prefrontal cerbral cortex Social thinking

Hypothalamus Attachment behaviours

Amygdala Emotional learning; decode emotional facial expressions

Fusiform gyrusMid temporal gyrus

Face recognitionRecognition of facial expression

Prefrontal Cortex Evidence• Prefrontal cortex: Evidence of functional under activation of

the PFC at rest and during task related performance in those with autism is unequivocal (Di Martino et al., 2009; Kennedy & Courchesne, 2008).

• Compatibility to theory-of-mind deficits and also multi tasking (Burgess, Veitch, Costello & Shallice, 2000; Burgess et al. 2007; Hill & Bird, 2006; Baron-Cohen, Leslie, & Frith, 1985).

• Help explains some of the: comorbidity between autism and ADHD; executive dysfunction model of autism (Ozonoff , Pennington and Rogers, 1991); central coherence theory (Frith, 1989).

Amygdala and Empathy• Blair (2008) considers the amygdala to be centrally involved in

empathy/recognising the mental state of others. Empathy deficit is a key concept of Baron-Cohen’s (2009) empathising-systemising model of autism…. “The ability to imagine and respond to the feelings of others”. Zero degrees of empathy (Borderline Personality Disorder, psychopathy).

• In autistic populations Bauman and Kemper (1985) found atypical cell density in the amygdalae with established reduced volume in the amygdalae. Amygdala/Prefrontal Cortex abnormality may help explain deficits in emotional-behavioural control, anger etc.

• Functionally, Baron-Cohen and colleagues has evidenced hypoactivation in the amygdala through fMRI during mentalising tasks using his well known 'reading the mind in the eyes' tasks (Baron-Cohen et al. 1999)

Brain overgrowth

• One frequently reported neuroanatomical feature of autism is a trajectory of generalised early brain overgrowth when aged 6–24 months. Other than increases in total brain volume, the amygdala is enlarged in young children with autism, although this enlargement is no longer present by adolescence. Early brain over growth tends to be reported more in boys. Additionally meta-analyses suggest some consistent neuroanatomical differences across the lifespan in both grey-matter (eg, amygdala, hippocampus, and precuneus) and white-matter structures (eg, arcuate and uncinate fasciculi). A reduction in the volume of the corpus callosum is also a fairly consistent finding.

Brain development: brain overgrowth and inadequate pruning

• Synapses important and change as learning takes place. New, wither, strength altered. Synaptogenesis (Blooming) especially childhood. Babies 1000’s every second. Bulk of addition up to about 2 years. Fewer added later in life. Too many formed so this leads to pruning and long-term reduction of synapses. A significant proportion of people with autism (approximately 20%) have been found to have statistically larger and heavier brains (cranium measurements and structural neuroimaging.) Brain overgrowth accelerates at 12 months and then continues during the first 2 years of life in parallel with the first behavioural identifiers of the disorder

Brain development: brain overgrowth and inadequate pruning

• Brain overgrowth tends to decelerate in autistic individuals during middle

childhood and differences are often negligible by older age. Overgrowth of white matter. But underdevelopment in grey matter at cellular level

• Many neuroscientists believe this is caused by inadequate cortical pruning of the brain during the early years of life

• Interaction between the immune and the nervous systems is substantial throughout life. Frequency of immunological anomalies is increased in individuals with autism and their families. In autism, altered immune processes affect a wide array of neurodevelopmental processes (eg, neurogenesis, synaptogenesis, and synaptic pruning)

Gender

• A male predominance is a consistent epidemiological finding that has aetiological and females with autism might have been under-recognised. Empirical data suggest high-functioning females are diagnosed later than males are, and indicate a diagnostic bias towards males. Females need more concurrent behavioural or cognitive problems than males do to be clinically diagnosed. It could imply female-specific protective effects, such that females would have to have a greater aetiological (genetic or environmental) load than would males to reach the diagnostic threshold.

The extreme male brain theory

• Autism as an extreme case of the male brain, those individuals in whom systemizing is better than empathizing (according to psychometrical tests). • Systemize = develop internal rules to handle events inside the brain.• Empathize = rules handling events generated by other agents. • Explains why more boys have autism• Theory of mind: autism arises from inability to ascribe mental states to

oneself and others, as shows in the results of tests for reasoning about others' motivations.

Foetal testosterone Cambridge University (2013)

• Because autism and Asperger’s Syndrome affect boys far more often than girls, Cambridge neuroscientists have been driving research into foetal testosterone in order to examine its effects on brain development and postnatal behaviour. They have analysed the effects of prenatal testosterone levels, produced by the foetus and measured via amniocentesis during the first trimester of pregnancy, on autistic behaviour. Foetal testosterone shapes brain development to alter an individual’s cognitive profile by binding to androgen receptors in the brain, the amygdala being one region that is rich in such receptors. Strikingly, they have shown that higher prenatal testosterone levels are associated with reduced social skills but superior attention to detail in infants.

• Boys, it seems, can develop autism from a relatively small genetic hit. It takes more of a genetic wallop, though, to cause autism in girls – so when they do get it, they're worse off. The same explanation holds true, researchers think, for the gender imbalance in ADHD, intellectual disabilities and schizophrenia. This finding, in a study of more than 16,000 people, confirms that autism is not simply being missed in females – it is actually occurring less often. There are about seven males with mild autism for every female, though the gender gap is much smaller at the more severe end of the spectrum. (American Journal of Human Genetics, 2014) • http

://www.usatoday.com/story/news/nation/2014/02/27/autism-girls-versus-boys/5862747/

• The study also showed that the mutations behind the autism are either new ones that develop in the child, or come from the parents – most likely from the mother. A man who is severely affected by an autism-related genetic glitch is more likely to have trouble forming relationships and therefore less likely to have children, researchers said, so less likely to pass the mutation on. A woman, who can have the glitch without noticing it, would be more likely to reproduce and therefore pass on the mutation

References

Bauman, M., & Kemper, T. L. (1985). Histoanatomic observations of the brain in early infantile autism. Neurology, 35, 866-874.Bauman, M., & Kemper, T. L. (1988). Limbic and cerebellar abnormalities: Consistent findings in infantile autism. Journal of Neuropathology and Experimental Neurology, 47, 369.Bennetto, L., Pennington, B. F., & Rogers, S. J. (1996). Intact and impaired memory functions in autism. Child Development, 67, 1816-1835.Boucher, J. (1977). Alternation and sequencing behavior and the response to novelty in autistic children. Journal of Child Psychology & Psychiatry, 18, 67-72.Boucher, J. (1988). Word fluency in high-functioning autistic children. Journal of Autism and Developmental Disorders, 18, 637-645.Casanova MF (2007) The neuropathology of autism. Brain Pathology 17: 422–33Courchesne, E., Yeung-Courchesne, R., Press, G. A., Hesselink, J. R., & Jernigan, T. L. (1988). Hypoplasia of cerebellar vermal lobule-Vi and lobule-Vii in autism. New England Journal of Medicine, 318, 1349-1354.Dawson, G., Klinger, L. G., Panagiotides, H., & Lewy, A. (1993). Electrophysiological evidence for frontal lobe involvement in the social impairments of individuals with autism. Paper presented at biennial meeting for SRCD, New Orleans, LA, 25-28 March.Frith, U. (1972) Cognitive mechanisms in autism: experiments with color and tone sequence production. Journal of Autism and Child Schizophrenia, 2, 160-173.Gaffney, G. R., Kuperman, S., Tsai, L. Y., & Minchin, S. (1989). Forebrain structure in autism. Journal of the American Academy of Child and Adolescent Psychiatry, 28, 534-537.George, M. S., Costa, D. C., Kouris, K., Ring, H. A., & Ell, P. J. (1992). Cerebral blood flow abnormalities in adults with infantile autism. Journal of Nervous & Mental Disease, 180, 413-417.Geschwind DH (2008). Autism: many genes, common pathways? Cell 135: 391–5; Müller RA (2007) The study of autism as a distributed disorder. Mental Retardation and Developmental Disabilities Research Reviews 13 (1): 85–95

• Guerts, H. M., Verté, S., Oosterlaan, J., Roeyers, H., & Sergeant, J. A. (2004). How specific are executive functioning deficits in attention deficit hyperactivity disorder and autism? Journal of Child Psychology and Psychiatry, 45, 836-854.

• Hetzler, B. E., & Griffiin, J. L. (1981). Infantile autism and the temporal lobe of the brain. Journal of Autism and Developmental Disorders, 11, 317-330.

• Hill, E. L. (2004). Executive dysfunction in autism. Trends in Cognitive Sciences, 8, 26-32.• Hill, E. L. (2004). Evaluating the theory of executive dysfunction in autism. Developmental Review, 24, 189-233.• Horwitz, B., Rumsey, J. M., Grady, C. L., & Rapoport, S. I. (1988). The cerebral metabolic landscape in autism: Intercorrelations of regional

glucose utilization. Archives of Neurology, 45, 749-755.• Hughes, C. (1998). Finding your marbles: Does preschoolers’ strategic behavior predict later understanding of mind? Developmental

Psychology, 34, 1326-1339.• Hughes, C., & Russell, J. (1993). Autistic children’s difficulty with mental disengagement from an object: Its implications for theories of

autism. Developmental Psychology, 29, 498-510.• Hughes, C. et al. (1997). Executive function in parents of children with autism. Psychological Medicine, 27, 209-220.• Jarrold, C., Boucher, J., & Smith, P. K. (1996). Generativity deficits in pretend play in autism. British Journal of Developmental Psychology,

14, 275-300.• Koegel, R. L., & Schreibman, L. (1977). Teaching autistic children to respond to simultaneous multiple cues. Journal of Experimental Child

Psychology, 24, 299-311.• Koshino, H., Carpenter, P. A., Minshew, N. J., Cherassky, V. L., Keller, T. A., & Just, M. A. (2005). Functional connectivity in an fMRI working

memory task with high-functioning autism. Neuroimage, 24, 810-821. • Lewis, V., & Boucher, J. (1991). Skill, content and generative strategies in autistic children’s drawings. British Journal of Developmental

Psychology, 9, 393-416.

Lovaas, O. I., Koegel, R. L., & Schreibman, L. (1979). Stimulus overselectivity in autism: A review of research. Psychological Bulletin, 86, 1236-1254.Luna, B. et al. (2002). Neocortical system abnormalities in autism. An fMRI study of spatial working memory. Neurology, 59, 834-840.Minshew, N. J., Goldstein, G., Muenz, L. R., & Payton, L. R. (1992). Neuropsychological functioning in nonmentally retarded autistic individuals. Journal of Clinical and Experimental Neuropsychology, 14, 749-761.Ohnishi, T. et al. (2000). Abnormal regional cerebral blood flow in childhood autism. Brain, 123, 1838-1844.Ozonoff, S. (1997). Components of executive function in autism and other disorders. In J. Russell (ed.). Autism as an Executive Disorder. Oxford: OUP.Ozonoff, S., Pennington, B. F., & Rogers, S. J. (1991). Executive function deficits in high-functioning autistic individuals: Relationship to theory of mind. Journal of Child Psychology and Psychiatry, 32, 1081-1105.Pennington, B. F., & Ozonoff, S. (1996). Executive functions and developmental psychopathology. Journal of Child Psychology and Psychiatry, 37, 51-87.Perner, J. (1998). The meta-intentional nature of executive functions and theory of mind. In P. Carruthers & J. Boucher (eds.). Language and thought: Interdisciplinary themes. Cambridge: Cambridge University Press.Prior, M. R., & Hoffman, W. (1990). Brief report: Neuropsychological testing of autistic children through an exploration with frontal lobe tests. Journal of Autism and Developmental Disorders, 20, 581-590.Salmond, C. H. et al. (2003). Investigating individual differences in brain abnormalities in autism. Philosophical Transactions of the Royal Society of London, B, 358, 405-413.Zilbovicius, M., Garreau, B., Samson, Y., Remy, P., Barthelemy, C., Syrota, A., & Lelord, G. (1995). Delayed maturation of the frontal cortex in childhood autism. American Journal of Psychiatry, 152, 248-252.