Infant excitation/inhibition balance interacts with executive attention to predict autistic traits in childhood
Authors: Carter Leno Virginia , Begum-Ali Jannath , Goodwin Amy , Mason Luke , Pasco Greg , Pickles Andrew , Garg Shruti , Green Jonathan , Charman Tony , Johnson Mark H. , Jones Emily J. H. ,   the EDEN, Vassallo Grace , Burkitt-Wright Emma , Eelloo Judith , Gareth Evans D , West Siobhan , Hupton Eileen , Lewis Lauren , Robinson Louise , Dobbie Angus , Drimer Ruth , Bethell Helen , Jones Rachel , Musson Susan , Prem Catherine , Splitt Miranda , Horridge Karen , Baralle Diana , Redman Carolyn , Tomkins Helen , Bhojwani Ankita , Connelly Shannon , Conti Francesca , Evans Beth , Jackson Meg , Powell Emily ,   STAARS Teams, Agyapong Mary , Bazelmans Tessel , Dafner Leila , Ersoy Mutluhan , Gliga Teea , Haartsen Rianne , Halkola Hanna , Hendry Alexandra , Holman Rebecca , Kalwarowsky Sarah , Kolesnik Anna , Narvekar Nisha , Taylor Chloë 
Published: December 2022

Abstract
Background
Autism is proposed to be characterised by an atypical balance of cortical excitation and inhibition (E/I). However, most studies have examined E/I alterations in older autistic individuals, meaning that findings could in part reflect homeostatic compensation. To assess the directionality of effects, it is necessary to examine alterations in E/I balance early in the lifespan before symptom emergence. Recent explanatory frameworks have argued that it is also necessary to consider how early risk features interact with later developing modifier factors to predict autism outcomes.

Method
We indexed E/I balance in early infancy by extracting the aperiodic exponent of the slope of the electroencephalogram (EEG) power spectrum (‘1/f’). To validate our index of E/I balance, we tested for differences in the aperiodic exponent in 10-month-old infants with (n = 22) and without (n = 27) neurofibromatosis type 1 (NF1), a condition thought to be characterised by alterations to cortical inhibition. We then tested for E/I alterations in a larger heterogeneous longitudinal cohort of infants with and without a family history of neurodevelopmental conditions (n = 150) who had been followed to early childhood. We tested the relevance of alterations in E/I balance and our proposed modifier, executive attention, by assessing whether associations between 10-month aperiodic slope and 36-month neurodevelopmental traits were moderated by 24-month executive attention. Analyses adjusted for age at EEG assessment, sex and number of EEG trials.

Results
Infants with NF1 were characterised by a higher aperiodic exponent, indicative of greater inhibition, supporting our infant measure of E/I. Longitudinal analyses showed a significant interaction between aperiodic slope and executive attention, such that higher aperiodic exponents predicted greater autistic traits in childhood, but only in infants who also had weaker executive functioning abilities.

Limitations
The current study relied on parent report of infant executive functioning-type abilities; future work is required to replicate effects with objective measures of cognition.

Conclusions
Results suggest alterations in E/I balance are on the developmental pathway to autism outcomes, and that higher executive functioning abilities may buffer the impact of early cortical atypicalities, consistent with proposals that stronger executive functioning abilities may modify the impact of a wide range of risk factors.