Sex Differences in ASD

Question 1

Write an introduction for how prenatal hormone exposure accounts for the development of ASD

Answer 1

• Autism Spectrum Disorder (ASD) is a complex developmental condition affecting 1% of the UK with a large male biase in diagnosis with 5:1 ratio (National Autistic Society, 2018).
• Although considered a multifactorial disorder with interactions between genetic and non-genetic risk factors (Tidy, 2016), prenatal hormone exposure may partially account for the development of ASD, under the foetal testosterone (fT) theory.
• This states fT influences brain development to produce a certain brain type that results in the characteristic symptoms of ASD (Lakhlani, 2019).
• This essay discusses the sex differences in neurotypical individuals and their brain types under the empathising-systemising (E-S) theory, and how prenatal hormone exposure alters the brain towards an extreme male brain type thought to underlie ASD.

Question 2

How is Autism Spectrum Disorder diagnosed?

Answer 2

• ASD is diagnosed in the presence of two universal dimensions:
  
  • ​Persistent deficits in social communication and interaction across multiple contexts;
  • Restricted, repetitive patterns of behaviour, interests, or activities (APA, 2013)
• The disorder can be associated with any level of general intelligence, with presentation ranging from subtle problems of understanding and impaired social function to severe disabilities, existing along a continuum of minimal to severe traits (Tidy, 2016).
• Classical autism includes learning difficulties and language delay alongside the two dimensions (Baron-Cohen et al., 2011).

Question 3

Outline the sex differences in neurotypical individuals

Answer 3

• Behavioural, cognitive, and neuroanatomical dichotomies exist between neurotypical males and females at a population level (Lakhlani, 2019).
• Behavioural and cognitive include:
  
  • ​Males perform better on visual-spatial tasks
  • Males demonstrate superior mathematical ability
  • Females demonstrate superior verbal skills
  • Males show more aggression (Maccoby & Jacklin, 1974)
• Neuroanatomical include (Ruigrok et al., 2014):
  
  • ​Males have higher total brain volume
  • Males have larger limbic areas (spatial memory) and left posterior cingulate gyrus (attention)
  • Females have larger language-related areas in the right hemisphere
• Connectome maps (Ingalhalikar et al., 2014)​
  
  • ​Average male brain features stronger intra-hemispheric connections, consistent with previous fMRI studies reporting greater intra-hemispheric activity in males when performing spatial tasks.
  • Average female brain features stronger inter-hemispheric connections, consistent with previous fMRI studies reporting greater inter-hemispheric connects in females on language tasks.

Question 4

Discuss the empathising-systemising theory of sex differences

Answer 4

• The E-S theory describes a spectrum of brain types that accounts for the sex differences in behaviour and cognition.
• It centres around two dimensions (Baron-Cohen, 2002):
  
  • ​Empathising is the ability to indentify and understand thoughts and feelings of others and respond with appropriate emotions;
  • Systemising is the interest in strength of systems and desire to analyse and construct input-operation-output relations to formulates rules
• Using Systemising Quotient and Empathising Quotient to assess the two dimensions, on average males scored higher than females on systemising, and females scored higher than males on empathising.
• The theory outlines five brain types across a population (Baron-Cohen, 2002):
  
  • ​Type S: systemising is significantly better than empathising
  • Type E: empathising is significantly better than systemising
  • Type B: the two dimensions are equally balanced
  • Extreme Type S: enhanced systemising with impaired empathising
  • Extreme Type E: enhanced empathising with impaired systemising

Question 5

How does E-S theory explain the behavioural and cognitive neurotypical sex differences noted by Maccoby & Jacklin (1974)?

Answer 5

• Mathematics and visual-spatial tasks are considered systemising
• Language skills are considered to require empathising
• Aggression is said to need reduced empathy, with murder as the ultimate lack of empathy
• ‘Male-on-male’ homicide occurs at 30-40 time as frequently as ‘female-on-female’ homicide across 700 years of homicide records (Baron-Cohen, 2002)

Question 6

Outline the behavioural and cognitive differences between autism and neurotypical individuals and the EMB theory

Answer 6

• In addition to neurotypical sex differences, ASD individuals (male and female) are observed to show hypermasculinity of behaviour, cognition, and neuroanatomy (Baron-Cohen et al., 2011)
• Autistic individuals score even higher than neurotypical males on systemising
• Autistic individuals score even lower than neurotypical males on empathisingm including eye contact and language assessments (Baron-Cohen et al., 2002).
• Neurotypical male infants have larger brains than females, which is even larger in ASD (Baron-Cohen, 2002), especially at the 3-year point when the majority of ASD is diagnosed (Baron-Cohen et al., 2011).
• These observations have formed the basis of the Extreme Male Brain (EMB) hypothesis of autism, stating ASD arises from an individual’s brain becoming masculinised towards the extreme Type S brain type (Baron-Cohen, 2002).

Question 7

Discuss the role of testosterone in neural development

Answer 7

• Testosterone is the primary gonadal hormone in males, produced at several times the magnitude from the testes in males versus the small production from the ovaries and adrenal glands in females (Burger, 2002).
• Human males experience three surges of testosterone:
  
  • ​Foetal between 8-24 weeks gestation
  • Neonatal soon after birth till 4-6 months
  • Pubertal testosterone
• fT has an ‘organisational’ effect on the brain, producing sex differences in neuroanatomy and behaviour (Arnold, 2009).
• fT is associated with rightward asymmetrical thickening of the corpus callosum, which projects to visuospatial and language brain regions; it averts neuronal apoptosis, modulates neurotransmission, and increases dendritic spine formation (Baron-Cohen et al., 2011).
• Girls with congenital adrenal hyperplasia (CAH) have been observed to display ‘tomboyish’ behaviours and cognitions (Hines & Kauffman, 1994). 95% of CAH involves 21-hydroxylase deficiency resulting in cortisol +/- aldosterone deficits, with compensatory overproduction of androgens/testosterone (NORD, 2018).
• Experimental testosterone manipulation can partially reverse these differences.
• Male rats perform better on radial arm and Morris maze tests (both systemising tests of spatial learning and memory) (Roof et al., 1993).
• This difference is eliminated upon castration of males or treating females with neonetal testosterone (Baron-Cohen, 2005).
• Similar manipulations have sex-reversed brain region volume and number/size of cells within a brain region (Arnold, 2009).

Question 8

How is testosterone suggested to produce ASD?

Answer 8

• Therefore, prenatal hormone exposure to foetal testosterone modifies the brain type towards a more typical male brain type.
• Under the EMB theory, this requires higher exposure to fT to bring about the changes resulting in ASD.
• Evidence supporting this can be seen in data surrounding digit ratio (2D:4D), puberty, and amniotic fluid levels.
  
  • ​2D:4D is widely accepted as a proxy measure of fT, with lower ratios correlating to higher fT. Males have lower ratios than females, with ASD showing even lower ratios (Teatero & Netley, 2013)
  • Low 2D:4D is associated with ASD and other male-bias neuropsychiatric conditions (Teatero & Netley, 2013)
  • Autistic males are at increased risk of precocious puberty (Baron-Cohen et al., 2005)
  • Cambridge Foetal Testosterone Project (Baron-Cohen et al., 1998, 2011) Amniotic fT is inversly associated with social domains (eye contact, vocabulary, empathy), and positively associated with non-social domains (narrow interests, attention detail, and systeming) (Baron-Cohen et al., 2011)
• Androgen dysregulation is seen in ASD individuals and non-affected relatives (Baron-Cohen et al., 2011)

Question 9

Describe how biological sex affects autism neurobiology

Answer 9

• Lai et al (2013) describes how autistic females show reduced female-typical play and behaviours, have higher serum testosterone levels, elevated risk of androgen-related pathology (PCOS and late-onset menarche), and masculinised physical features.
• Both male and females with autism have elevated testosterone precursors, with a greater difference from typical individuals in females.
• This supports the EMB theory in that typical male brain (Type S) is more similar to the EMB and requires less neural changes mediated by fT than the typical female brain (Type E).
• Lai et al (2013) found neuroanatomical ‘masculinisation’ only in high-functioning autistic females. They postulated this may result from the larger proportional increase in fT exposure as typical females produce little testosterone.
• Importantly, their research utilised high-functioning autism, so does not apply to all spectrums of ASD severity.

Question 10

Discuss the criticism of E-S and EBM theories

Answer 10

• A common criticism of E-S and EBM theories is the use of small sample sizes in their initial research (Greenberg et al., 2018).
• Newer research has reproduced the findings with data from over 670,000 individuals (Greenberg et al., 2018).
• Their results report that on average: typical females score higher on EQ compared to typical males; typical males score higher on SQ compared to typical females; and autistic individuals of either sex display ‘masculinised’ results along the E-S dimensions.
• This difference accounted for 19 times the variance in autistic traits compared to other demographic variables such as sex (Greenberg et al., 2018).

Question 11

Discuss the underdiagnosis of female ASD

Answer 11

• Beyond the sex-differences in E-S dimensions thought to contribute to ASD, the male bias is alternatively viewed as an artefact of diagnostic difficulties.
• Diagnosing ASD in females is challenging, particularly if occuring alongside comorbid anorexia or EUPD (Baron-Cohen et al., 2011).
• Both these conditions involve exercising excessive control over the environment or people, and some degree of self-centredness (Baron-Cohen et al., 2011).
• Given data supports the average female is better at empathising than systemising compared to males, girls may better conform socially or imitate normality to mask their ASD (Baron-Cohen et al., 2011).
• Finally current diagnostic tools such as ADOS and ADI-R may fail to detect the subtle aspects of autism in females (Baron-Cohen et al., 2011).

Question 12

Write a conclusion on the sex differences in the brain and ASD

Answer 12

• In conclusion, ASD is a greatly heterogeneous neurodevelopmental condition characterised by two universal traits of persistent deficits in social communication and interaction across multiple contexts; and restrictedm repetitive patterns of behaviour, interests, or activities.
• It is widely regarded as a multifactorial disorder of genetic and non-genetic risk factors.
• Foetal testosterone is one of these risk factors, and is thought to induce certain neuroanatomical changes that result in the behavioural and cognitive impairments in ASD.
• This shifts the neurotypical male or female brain type towards the extreme male brain type.
• Typical male brain (appearing more often in male sex) is better at systemising than empathising, whereas the typical female brain (appearing more often in female sex) is the opposite.
• The EMB seen in ASD reflects even superior systemising and even inferior empathising than the typical male brain, based on observations of autistic individuals on EQ and SQ assessments.
• The gender bias of 5:1 in favour of males is said to reflect the small shift required to alter the typical male brain into the EMB, in comparison to the large shift required to alter the typical female brain into the EMB.
• Finally, it is important to stress this is not unanimously accepted, as other biological theories exist such as the X and Y chromosome theories, and the notion the sex difference may be an artefact of bias diagnostic tools.
• Baron-Cohen’s theories provide some insight, but more replicable research is necessary to further uncover the pathology of autism, particularly seeing if the sex differences seen in typical male brains, displaying certain enlarged brain areas and stronger intra-hemispheric connections is exaggerated in ASD.