4. Plan de marketing
4.17 Estrategia de marketing
3.3.2.1 Protective effect of looking behaviour against neural vulnerability
To evaluate whether looking behaviour had a protective effect against brain vulnerability during social attention, I first computed a composite score between Ms duration and Nc mean amplitude, as previously explained (see section 3.2.3). I then divided the ‘neural vulnerability composite’ data for the entire sample in four quartiles, such that the first quantile included infants with reduced attention to faces than Noise and the fourth quartile included infants with more enhanced attention to the face. Figure 3.8 illustrates the proportion of HR children in each neural vulnerability quartile for the three outcome groups.
Nc mean amp. Nc peak lat. Ms mean GFP Ms duration Diseng. RT Effortful control Attentive brain state Looking time at the gazed- at object Peak look at the face Risk group Phase 0.16 0.50 -0. 30 -0.37 -0.68 -0.37 -0.37 -0. 17 1.00 0.17 0.27 0. 50 T1 (8 months) T2 (14 months) T4 (3 years)
Figure 3.8 Illustration of the proportion of HR children in each of the three outcome groups in the four quartiles of neural vulnerability, estimated as the composite value of Nc mean amplitude and Ms duration difference between the FD and the Noise condition. The 1st quartile includes the infants with reduced attention engagement to faces with direct gaze than noise, while the 4th quartile includes the infants with enhanced neural responses to noise than to face (i.e. less social attention engagement). The blue part of the bars indicates the proportion of HR-TD children, the orange part of the bars indicates the proportion of HR-Aty children, the red part of the bars indicates the proportion of HR-ASD children.
When comparing HR children with and without ASD who showed reduced neural responses to the face compared to the non-social stimulus (high neural vulnerability) with those with enhanced neural responses to faces (low neural vulnerability), there was no significant effect of ASD group in peak look duration at the face (F(1,74)=0.051, p=0.821, h2=0.0001) and looking time at the gazed-at object (F(1,73)=2.773, p=0.100, h2=0.097). There was no effect of neural vulnerability on the peak look at the face (F(1,74)=0.013, p=0.909, h2=0.002) while a significant effect was observed for the proportion of looking time at the gazed-at object in the gaze following task (F(1,73)=9.946, p=0.002, h2=0.001). The interaction between outcome group and neural vulnerability was non-significant for both eye-tracking measures (peak-look at the face: F(1,74)=0.046, p=0.831, h2=0.0006, looking time at the gazed-at object: F(1,73)=0.064, p=0.802, h2=0.0009).
These analyses indicated that peak look duration at a static face stimulus during a face pop-out task at 14 months is not different between infants with and without later ASD, independently from their level of neural vulnerability defined as atypical brain responses to faces and non- social stimuli at 8 months. Differently, HR-ASD infants showed significantly reduced attention engagement with the gazed-at object compared to HR-noASD infants irrespective of neural vulnerability group. This indicated that looking behaviour during social attention at T2 did not
have a protective value for infants who showed more enhanced and prolonged neural responses when attending to faces than non-social stimuli at T1.
Figure 3.9 Barplots indicating the interaction between neural vulnerability and ASD diagnosis in the HR children. Differences in peak look duration at the face in the face pop-out task (a) and proportion of looking time at the gazed-at object in the gaze following task (b) are displayed by outcome group for HR infants considered at high and low neural vulnerability based on the difference in neural measures when looking at FD compared to Noise. In all plots, error bars represent standard errors.
3.3.2.2 Sex-specific protective effect of looking behaviour against familial/genetic risk
Another way to uncover potential protective factors is to compare individuals at risk who have ‘better than expected outcome’ with individuals with no risk factors (Szatmari, 2018). In this analysis, I examined whether exceptional attention in social contexts at 14 months was observed in infants at high risk who did not develop the core symptoms of ASD at three years (HR-TD and HR-Aty), compared to LR children. This effect was tested in interaction with sex, to uncover the presence of sex-specific mechanisms.
When examining the peak look duration at the face, I found a significant effect of group (F(1,170)=6.207, p=0.003, h2=0.048). Post-hoc analyses revealed that HR-Aty (p=0.004) and HR- TD (p=0.019) stared for longer at the face than LR infants. No difference was observed between the two HR groups (p=0.576). There was no effect of sex (F(1,170)=0.004 p=0.950, h2=0.0002) nor interaction between sex and group (F(1,170)=1.062 p=0.348, h2=0.012), not confirming the idea of a protective value of this looking behaviour for girls at high familial risk for ASD. The effect of group on the proportion of looking time at the gazed-at object was non-significant (F(1,163)=2.363, p=0.126, h2=0.059). There was a main effect of sex (F(1,163)=2.363, p=0.126,
b a
h2<0.0001) but no significant interaction between group and sex (F(1,163)=1.341, p=0.264, h2=0.016).
In order to control whether results were influenced by lower cognitive abilities in the HR-Aty group, I performed the same analyses introducing MSEL composite score at T2 as covariate. The same pattern of result was observed, with a main effect of outcome for the peak look at the face (F(1,167)=6.178, p=0.002, h2=0.047) and not for looking time at the gazed-at object (F(1,159)=1.977, p=0.142, h2=0.063), and no effect of sex or interaction between outcome and sex (all ps>0.115, all h2 <0.017). The relationship between cognitive abilities and behavioural correlates of social attention was not significant for the face pop-out (F(1,167)=0.006, p=0.938, h2<0.0001) and approaching significance for gaze following measure (F(1,159)=3.377, p=0.068, h2=0.021).
In sum, these analyses revealed that longer peak look durations at a static image of a face in a face pop-out task were associated with risk for ASD such that they are observed in infants who did not show core ASD symptoms at three years, differently from the LR group. Looking time at the object another person is gazing at seemed to be an early marker of ASD specifically. In fact, individuals at risk who underwent a typical developmental trajectory did show higher engagement to the gazed-at object compared to low-risk infants (see Figure 3.10b), but this effect was not significant probably due to the large standard errors. Overall, I found no evidence for sex differences in social attention measures suggesting a different resilience mechanism for male and female infants at high risk for ASD.
Figure 3.10 Barplots indicating the interaction between sex and outcome group for the two eye- tracking measures of social attention. Differences in peak look duration at the face in the face pop- out task (a) and proportion of looking time at the gazed-at object in the gaze following task, adjusted for the effect of phase, (b) are displayed for 14-month-old boys and girls at low familial risk (LR, in green), high familial risk for ASD with typical development at 3 years (HR-TD, blue) and high familial risk who showed features of atypical development at 3 years but no core ASD symptoms (HR-Aty, in orange). For comparison, mean scores for boys and girls with emerging ASD, not included in this analysis, are shown in transparent red. Error bars represent standard errors.
3.4 DISCUSSION
In this chapter, a series of analyses was conducted in order to understand the relationship between neural and behavioural measures previously indicated as early signs of atypical developmental trajectory in children at familial risk for ASD. In Chapter 2 I identified correlates of atypical engagement of attentive brain states in response to faces with direct gaze versus non-social control stimuli (Noise) at around 8 months of age, which have been found to be predictive of later ASD in the HR group. I built on these results to explore the possibility that these neural atypicalities, possibly disrupting the development of neural circuits devoted to attention in general and social attention specifically, might lead to atypical looking behaviour at 14 months of age, which in turn has been proposed to precede the onset of social and cognitive difficulties associated with neurodevelopmental disorders. I used SEM to understand the possible role of prolonged peak look duration at face stimuli in a face pop-out task, reduced looking times at the gazed-at object in a gaze following task, and difficulties in disengagement from a central stimulus in developmental trajectories observed on 247 infants who participated
b a
in BASIS Phase 1 and 2. I tested four different pathways to examine trajectories to four dimensional outcomes: social adaptive behaviour, autistic traits and language abilities at three years and effortful control at two years. Early attentive brain states were predictive of socialization difficulties but also other domains of the ASD phenotypes such as language and, to a lesser extent, effortful control. This suggests that early neural responses indicating reduced engagement when attending to faces and enhanced engagement to non-social visual stimuli are likely to reflect domain-general deficits rather than disruptions exclusively in the social domain. No evidence for a relationship between attentive brain state and peak look duration at the face or disengagement was found. Those two measures of atypical looking behaviour were associated with language skills at age 3 independently from the factor representing neural correlates of social attention. These findings might indicate that they do not play a major role in the path to ASD social traits. On the contrary, suggestive evidence for a partial mediation effect of the gaze following measure on the relationship between early attentive brain states to FD versus Noise and later social adaptive skills was observed. Moreover, this early marker seemed to be mainly associated with both social and non-social autistic traits. Thus, early disruptions in responding to joint attention might play a role in the path towards ASD symptoms and could be candidate targets for intervention.
A further investigation was conducted on the same measures to test the possible role of different aspects of looking behaviour as protective factors against brain vulnerability. I found no suggestive evidence for this hypothesis, although the analyses should be considered as preliminary given that they were limited by unbalanced group sizes. Last, the present study revealed no evidence for sex-specific mechanisms of resilience involving exceptionally high visual social attention behaviour protecting 14-month-olds at high genetic vulnerability from developing core ASD symptoms. However, descriptively I observed that this early marker might reflect protective mechanisms for HR siblings who have a typical outcome at three years.