DEFINICIÓN Y CARACTERÍSTICAS

In order to understand how genetic/epigenetic factors contribute to ASD and autistic traits, a powerful approach is to study early postnatal development to better understand causal paths mediating the gene-ASD link, and the emergence of ASD traits (Messinger et al., 2013). This approach is based on the idea that by studying defined components of cognition in infants at genetic risk we could identify developmental features associated with candidate biological pathways (Johnson & Pasco Fearon, 2011).

Siblings of children with ASD are considered at high risk for ASD. In fact, the recurrence rate of ASD outcome in younger siblings of children with ASD is nearly 20% (Ozonoff et al., 2011), that is impressively higher than the population rate of 1% (Baird et al., 2006). Moreover, first-degree relatives of individuals with ASD are more likely to share some phenotypic features with their affected relatives, suggesting that common familial factors might influence behavioural traits (Dalton, Nacewicz, Alexander, & Davidson, 2007; Lyall et al., 2014; Scheeren & Stauder, 2008; Wallace, Sebastian, Pellicano, Parr, & Bailey, 2010; Wheelwright, Auyeung, Allison, & Baron- Cohen, 2010). The clever idea at the base of the infant-sibling design is to recruit families with an older child with ASD who also have a newborn child, and follow up her development with a series of lab-based assessments and parent interviews until she reaches an age at which stable diagnosis of ASD can be made (Ozonoff et al., 2015). Thus, the study of siblings of children with ASD offers opportunities to understand why behavioural symptoms of a neurodevelopmental disorder emerge in some cases and not in others and to investigate protective and risk factors at a genetic, neural and behavioural level (Elsabbagh & Johnson, 2010).

1.1.3.1 From risk to outcome and from outcome to risk

Prospective longitudinal studies of infants with an older sibling with ASD (high-risk infants, HR) have examined how behavioural symptoms unfold over developmental time. Such studies typically followed infants from close to birth to age 3, when they underwent diagnostic assessment with a team of experienced research clinicians. During the multiple lab visits which are carried out over the first three years of life, measures of infants’ developmental features are usually obtained from parent reports, researcher-administered standardised behavioural assessments and eye-tracking and neuroimaging recording during experimental tasks. Data is then analysed retrospectively based on the child’s diagnostic status at the outcome visit (Elsabbagh & Johnson, 2010).

Perhaps surprisingly, infant-sibling designs revealed that 6- to 8-month-old infants who later receive a diagnosis of ASD appear to be typically developing at the behavioural level (Jones et al., 2014). However, relative to infants with a neurotypical outcome, in the second year of life infants with emerging ASD show gradual declines in social interest and delayed or slower communication development that gradually accumulate (Ozonoff et al., 2014). By 14 months, behavioural measures of early signs of ASD begin to show some predictive validity for a later diagnosis (Bussu et al., 2018), and by 24 months a diagnosis is often possible (Szatmari et al., 2016). Thus, the study of infant siblings provided two fundamental insights about ASD: 1) the period between 8 and 24 months is particularly critical for identifying the causal processes involved in ASD, and 2) the use of dimensional neurocognitive measures as opposed to categorical diagnosis might be strategic to deeply understand the dynamic interaction between different functions characterising typical and atypical trajectories.

1.1.3.2 Uncovering early neurocognitive pathways to ASD

The use of neuroimaging, eye-tracking, measures of physiological response such as heart-rate and skin conductance in infant-sibling designs have been motivated by the need to have more direct measurements of cognitive and neural function, which might signal the onset of divergence developmental trajectories in children with ASD before overt social behaviours difficulties (Elsabbagh & Johnson, 2010).

One important discovery of infant-sibling studies is that patterns of early neural and behavioural atypicalities observed in the HR children might vary not only between individuals, but also within the same child across the first two years of life, possibly reflecting a complex interplay of risk and resilience mechanisms (Szatmari, 2018). In fact, HR infants who do not receive a diagnosis of ASD at three years can show, at earlier ages, an atypical (i.e. different from the low-risk – LR – control group, in the direction of the group with emerging ASD) response or an intermediate phenotypic manifestation (Gliga, Bedford, Charman, & Johnson, 2015a; Hendry et al., 2018; Lloyd-Fox et al., 2013; Wass et al., 2015). This observation suggests that some of these signs may be precursors of the disorder emerging as a result of vulnerabilities related to genetic or environmental risk factors, while others might represent compensatory responses which in some cases have protective value against the core ASD symptoms and in others, perhaps in combination with additional risk factors, lead to ‘cascading’ effects on different developmental features (Johnson, Gliga, Jones, & Charman, 2014).

Of interest, 10% of the HR infants who do not receive ASD diagnosis at 3 years manifest signs of mild to moderate developmental delay and 30% of them have elevated levels of autistic symptoms (compared to 3 and 15% of the LR children, respectively, Charman et al., 2017). These

children presumably carry some risk factors for ASD or neurodevelopmental disorder, but are, for still unknown reasons, resilient to developing the full syndrome (Szatmari, 2018).

Importantly, carefully following up developmental trajectories also allowed researchers to observe very early indicators of atypical pathways, such as age-specific differences in neural responses to social stimuli and progressive decline in social engagement at the level of subtle pattern of looking behaviour (Jones et al., 2016; Jones & Klin, 2013). However, another important consideration that arose from infant sibling studies is that early signs of atypical behaviour are not limited to the social domain but rather involve domain-general functions, such as attentional control and sensory processing (Gliga, Jones, Bedford, Charman, & Johnson, 2014). Accordingly, atypical characteristics of the brain of HR infants with later ASD can be seen in the first year of life and involve the primary visual cortex as well as sensorimotor areas (Hazlett et al., 2017; Lewis et al., 2017). This raised the possibility that ASD symptoms, particularly in the social domain, might emerge in the second year of life as a consequence of altered experience- dependent neuronal development due to disrupted sensorimotor and attentional experience (Piven, Elison, & Zylka, 2017).

Thus, mapping developmental trajectories of individuals at high risk to disturbances in brain development with a wide range of neurocognitive measures is likely to uncover what functions are more vulnerable and what elements of resilience play a role in the path taken.