Shifting Biology in ASD: Future Treatment Prospects – Assessment, Treatment and Research in Autism Spectrum Disorders
This article is based on the talk by Professor Grainne McAlonan at RCPsychIC2019. Prof McAlonan is a Specialty Doctor at the Adult ADHD Clinic and the Autism Assessment and Behavioural Genetics Clinic. She is also a Reader (Clinical) at The Institute of Psychiatry, King’s College London and Head of Research and Development for the Behavioural and Developmental Psychiatry Clinical Academic Group, King’s Health Partners.
- Autism spectrum disorder (ASD) is a life-long neurodevelopmental condition, currently estimated to affect between 1 and 1.5% of children and adults worldwide
- The key criteria for the diagnosis are impairments in social-communication, repetitive and restricted behaviours and interests, and atypical sensory responses
- Autism is highly complex and co-morbidity with other disorders occurs at high levels.
- It is unknown whether co-occurring conditions arise because autism provides a setting for mental health difficulties, or is there is another reason linked to the biology of autism which makes individuals vulnerable to co-occurring conditions.
- There are limited pharmacological interventions available to individuals with ASD, and unfortunately, patients often report that they receive no benefit from some of the conventional treatments for co-occurring conditions and they may be sensitive to side effects.
- For future interventions, we need to consider the target and what we know about autism. The EU-AIMS Longitudinal European Autism Project (LEAP) study asked the question of how two populations could be distinguished as individuals with and without autism. [Loth et al. 2017]
- Of the neurocognitive markers investigated, only ‘theory of mind’ showed a reasonable effect size, which means a considerable overlap between individuals with and without autism, and highlights the difficulty in identifying a target.
Theory of Mind (TOM) (also called mentalising or mindreading) refers to the ability to represent mental states, such as beliefs, desires, and intentions to predict and explain (others’ and own) behaviour.
- The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD.
- It has been considered that biological mechanisms may be different in ASD. As an example, by studying the excitatory-inhibitory (E-I) system in the brain, autism may be described as something that may affect how balance occurs in glutamate and GABA pathways. However, in-vivo samples of the living brain revealed little consistency across the studies published, whether in children or adults.
- A “Proof of Concept” study recently showed that responsivity to the E-I challenge is different in adults with autism and that the autistic brain is pharmacologically atypical [Ajram et al. 2017].
This unusual E–I responsivity in ASD may help explain other paradoxical findings from studies of the way people with ASD respond to E–I acting medications. For example, GABAA/benzodiazepine receptor agonists typically have an inhibitory effect in non-ASD populations, but can sometimes cause excitation in individuals with ASD.
- The causes of E–I responsivity differences is not known.
- ASD has been conceptualised as a developmental disconnection syndrome with underconnectivity between the prefrontal cortex and posterior brain network.
- Riluzole was able to establish functional connectivity between the two areas in high functioning adults with autism. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the CNS.
In conclusion, using [1H]MRS and fMRI, we found that E–I flux and functional connectivity of the prefrontal cortex are differentially regulated in adults with ASD compared with the controls. Importantly, inhibitory tone and functional connectivity can be shifted pharmacologically—and even in adults with ASD.[Ajram et al. 2017]