Autism spectrum disorder

Clinical picture (children and adolescents)

• Core domains: difficulties with social reciprocity, nonverbal communication (eye contact, gestures, joint attention) and forming relationships; repetitive movements, insistence on sameness, intense and restricted interests, sensory over- or under-responsiveness. The presentation varies greatly with intelligence and language level. A
• Early signs: in infants later diagnosed with autism, looking time to the eye region begins to decline between 2 and 6 months (Jones and Klin, 2013). Diagnosis can be made reliably around age 2 in most children, but many are diagnosed later. B
• Prevalence: median about 1% worldwide (100/10,000) in studies after 2012; estimates vary greatly with awareness, service capacity and methods (Zeidan et al., 2022). A
• Sex: the male-to-female ratio is about 4.5:1 in diagnosed samples and 3.3:1 in population screening; the true ratio is close to 3:1. Girls are missed more often and diagnosed later (Loomes et al., 2017). A
• Common co-occurring conditions: intellectual disability (median 33%; Zeidan et al., 2022), ADHD, anxiety, epilepsy, sleep and feeding problems, gastrointestinal complaints. A

Circuits and networks

• Amygdala: appraises the emotional significance of social stimuli; smaller volume in ENIGMA (van Rooij et al., 2018). A
• Superior Temporal Gyrus & Wernicke (superior temporal gyrus and sulcus): perception of biological motion, voice and speech; thinner temporal cortex in ENIGMA. A
• Temporoparietal Junction and Medial & Frontopolar Prefrontal Cortex: the circuit for understanding other minds (theory of mind). B
• Inferior Temporal & Fusiform Cortex (includes the fusiform face area): face processing. B
• Insula: inner bodily sensation (interoception) and emotional awareness; its link with alexithymia. B
• Putamen, Globus Pallidus, Nucleus Accumbens: smaller volumes in ENIGMA; linked to repetitive behaviors and social reward (van Rooij et al., 2018). A
• Cerebellum (especially Crus I, Crus II): cerebellar areas connected with social and language functions. B
• Networks: connectivity differences have been reported in the Default mode network (DMN) (thinking about oneself and others) and Salience network (salience) networks; findings are inconsistent across ages and methods. C

Neurotransmitter systems

• Serotonin (serotonin): elevated blood serotonin is an old and replicated finding; its clinical meaning is unclear. B
• Oxytocin: a regulator of social bonding; however, 24 weeks of intranasal oxytocin in 290 children did not improve social function compared with placebo (Sikich et al., 2021). B
• The GABA–glutamate balance (excitation–inhibition balance) is an important hypothesis; direct evidence in humans is limited. C
• Heritability is high: about 83% in Swedish twin and sibling data (Sandin et al., 2017). A

Imaging and neurobiological findings

• ENIGMA-ASD (1,571 autistic people, 1,651 controls, ages 2–64): smaller pallidum, putamen, amygdala and accumbens; thicker frontal cortex, thinner temporal cortex. Effects are small (d ≈ 0.1–0.2); cortical thickness differences peak around adolescence (van Rooij et al., 2018). A
• These are group-level differences; brain imaging cannot diagnose autism in an individual. A

Developmental course

• In high-risk infants (with an autistic sibling), rapid expansion of cortical surface area at 6–12 months precedes the increase in brain volume at 12–24 months; the volume increase is related to the emergence and severity of social symptoms (Hazlett et al., 2017; 15 infants later diagnosed). Small sample; not a screening tool. C
• Symptoms become clear in the first two years of life; language and adaptive skills follow very different courses through childhood. B

Treatment and the systems it targets

• Early intervention: naturalistic developmental behavioral interventions (NDBI) and developmental interventions have the strongest evidence for social communication; early intensive behavioral intervention is promising but needs higher-quality studies (Sandbank et al., 2020; 130 samples, ages 0–8). A
• There is no approved medication that treats the core symptoms. A
• For co-occurring irritability and aggression, risperidone (age 5 and up) and aripiprazole (ages 6–17) are FDA-approved; they act on dopamine and serotonin receptors. A
• Co-occurring ADHD, sleep problems and anxiety are treated with their own evidence-based treatments. B

Link to the book (The Green Walnut on the Couch)

• In the book (translated from the Turkish original):
  • PLAY system, clinical: "ADHD, social play in autism, traumatic play, depression".
  • Oxytocin pathway, where it appears in the book: "the neuroanatomy of CARE (Chapter 3), the distinction and overlap of CARE and LUST, prairie vole studies (Chapter 11), the effects of oxytocin that vary with the person and the context (Chapter 11), studies of intranasal oxytocin in autism (Chapter 7)."
  • Insula, clinical: "Alexithymia, somatization, interoception in autism".
  • The book also covers: atypical amygdala responses to social stimuli in autism (Chapter 7), social signal processing in autism (Chapter 7), the empathic insula response in alexithymia and autism (Chapter 2).

In the atlas

Regions

Core structures in bold.

Networks

Neurotransmitter pathways

Panksepp systems

References

1. Hazlett HC et al. (2017). Early brain development in infants at high risk for autism spectrum disorder. Nature, 542, 348–351. PMID: 28202961. Search PubMed
2. Jones W, Klin A (2013). Attention to eyes is present but in decline in 2–6-month-old infants later diagnosed with autism. Nature, 504, 427–431. Search PubMed
3. Loomes R, Hull L, Mandy WPL (2017). What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. JAACAP, 56(6), 466–474. DOI: 10.1016/j.jaac.2017.03.013.
4. Panksepp J et al. (1978). The biology of social attachments: opiates alleviate separation distress. Biological Psychiatry, 13(5), 607–618. Search PubMed
5. Sandbank M et al. (2020). Project AIM: Autism intervention meta-analysis for studies of young children. Psychological Bulletin, 146(1), 1–29. Search PubMed
6. Sandin S et al. (2017). The heritability of autism spectrum disorder. JAMA, 318(12), 1182–1184. Search PubMed
7. Sikich L et al. (2021). Intranasal oxytocin in children and adolescents with autism spectrum disorder. New England Journal of Medicine, 385, 1462–1473. Search PubMed
8. van Rooij D et al. (2018). Cortical and subcortical brain morphometry differences between patients with autism spectrum disorder and healthy individuals across the lifespan: results from the ENIGMA ASD Working Group. American Journal of Psychiatry, 175(4), 359–369. Search PubMed
9. Zeidan J et al. (2022). Global prevalence of autism: a systematic review update. Autism Research, 15(5), 778–790. DOI: 10.1002/aur.2696.