The sensory-first account of autism

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evidence linking early alterations in uni-and multisensory processing to a later autism diagnosis.These results are consistent with functional brain MRI data of older autistic participants showing differences in brain response to non-social stimuli and altered connectivity patterns emerging from primary sensory regions, with possible knock-on effects on multisensory integration (Robertson et al., 2014;Martínez et al., 2020).Collectively, these findings challenge historical theories of autism centred on social alterations by demonstrating that differences emerge in a broader sensory context and alterations are not restricted to the social domain.
Although brain correlates of categorical autism (diagnosis) and autistic traits are widespread, structural brain imaging studies on infants who go on to receive an autism diagnosis and older autistic individuals, as well as gene expression studies on post-mortem brain tissue, highlight the visual cortex as a potential hotspot for alterations emerging early in infancy and persisting across development (Robertson et al., 2014;Martínez et al., 2020;Gandal et al., 2022;Hazlett et al., 2017;Lewis et al., 2017;Jassim et al., 2021;Girault et al., 2022) (Fig. 1a).In line with this, we have found that infants who later develop autism symptoms have altered activation topography in the visual cortex when observing global motion (Hardiansyah et al., 2023) (Fig. 1b,c).Differences in global motion processing have previously been found in several studies of older children and adults with autism (e.g., (Robertson et al., 2014)), but observing such differences before symptom emergence adds a new developmental perspective on the potential role of these perceptual alterations.An outstanding question is whether these visual processing alterations reflect domain-specific neural differences or, perhaps, more general neural motifs (Robertson and Baron-Cohen, 2017) linked to the condition.Neural motifs, such as an altered connectivity distribution or excitation/inhibition imbalance, are generally thought to have a widespread influence across functional systems, from sensory to social domains.
It has been argued that higher-order autistic traits cannot be explained entirely by altered sensory representations, as by 'sensoryfirst' theories of autism, providing as argument the case of blind infants who generally do not develop cognitive features associated with the condition, such as difficulties with mentalizing (Robertson and Baron-Cohen, 2017).However, there is a fundamental difference between lacking sensory input completely and having systematic biases in sensory perception.For example, increased noise in a sensory system may alter the system in fundamental ways, such as prematurely closing 'critical periods' (Rubenstein and Merzenich, 2003).Further, it has been argued that a sensory perception atypicality should affect core language rather than pragmatics, while typically, the latter is more affected in autism than the former (Robertson and Baron-Cohen, 2017).However, alterations in visual perception (e.g., global motion processing) could affect a child's ability to process information from faces, which could impact the development of social communication more than core aspects of language.Further, sensory sensitivities may induce avoidance of noisy and unpredictable social environments, environments that other children may enjoy and from which they learn the pragmatics of social interaction and communication.Finally, it has been argued that if early sensory alterations in autism reflect general neural motifs affecting common canonical computations, that contradicts the 'sensory-first' idea (Robertson and Baron-Cohen, 2017).However, from a system-level developmental perspective, whether the underlying neural process is sensory-specific or not is of secondary interest.The developmental role of sensory perception remains crucial as it sets the stage for virtually all experience-dependent brain development (Rubenstein and Merzenich, 2003).Therefore, even if the jury is out on the precise underlying neurobiology of early markers of autism, developmentally speaking, it is time to embrace a 'sensory-first' view of the condition.
Although we argue that sensory processing is a useful umbrella term in understanding autistic development, it should be emphasized that it does not refer to a unitary biological process (He et al., 2023).Adding developmental evidence in support of this view, we recently observed, based on data from 570 5-month-old infant twins, that key dimensions of sensory processing were all associated with unique etiological influences, both in terms of genetic factors and influences from family environment (Fig. 2).The majority of these dimensions showed an association with autistic traits assessed at three years of age, in line with the 'sensory-first' perspective.The fractionable etiological structure underlying sensory processing early in life implies that any sensory oriented intervention (e.g., for autism) may benefit from narrowly targeting each dimension to be maximally effective.The findings can also explain seeming contra-intuitive observations, such as the same individual sometimes being reported as both hyper-and hypo-reactive to sensory stimulation.
It is likely that in infants with an elevated likelihood of developing autism, broad and heritable sensory dimensions, such as sensation sensitivity and sensation avoidance, interact with other factors, similar to how the general genetic background of mice moderates the effect of more potent genes linked to autism (Tabbaa et al., 2023) (Fig. 2).Such interplay may be an important contributor to heterogeneity not only in terms of autism symptoms but in frequently co-occurring symptoms such as anxiety, feeding and eating problems, and altered sleep patterns.Future work should investigate how autism-linked genetic mutations in humans interact with sensory background (e.g., operationalized as infant sensory profiles) to influence variability in developmental outcomes.Finally, data from older participants suggest that some aspects of sensory processing represent cross-diagnostic features (Isaacs and Riordan, 2020), while other aspects are specifically linked to autism (Neufeld et al., 2021).Thus, another key issue for future work is to investigate which types of early sensory processing differences are specific to autism and subgroups of autistic children.This could generate new leads on targets for early individualized intervention for autism and related neurodevelopmental conditions.

Funding statement
This work was funded by the Knut and Alice Wallenberg Foundation, Stiftelsen Sunnerdahls Handikappfond, and the Innovative Medicines Initiative 2 Joint Undertaking (grant 777394).This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI.The work was also supported by funds from the European Commission (H2020 project CANDY; grant 847818).Any views expressed are those of the author(s) and not necessarily those of the Fig. 1.Autism and the visual cortex.a) Post-mortem brain data suggest an anterior-to-posterior gradient of differences in gene-expression signatures of upregulated neural-immune genes and downregulated synaptic signalling genes, most pronounced in the visual cortex.From ref (Gandal et al., 2022).b) In typically developing infants, different types of visual information activate the visual cortex in distinct ways.c) Among these types, atypical (more lateralized) activation during observation of global motion is associated with having more symptoms of autism in toddlerhood.The Scatterplot shows both low and elevated likelihood groups combined.The insert shows an independent sample followed to 24 months.Panel b and c are adapted from ref (Hardiansyah et al., 2023).Fig. 2. Infant sensory profiles and developmental heterogeneity.Recent infant twin data suggest separability between sensory processing dimensions (sensation seeking, sensation avoiding, sensory sensitivity, and low registration) at a phenotypic as well as etiological level, with contributions from additive genetics and family environment that were unique to each dimension (Bussu et al., 2023).Most of these dimensions were correlated with autistic traits in toddlerhood.Individual 'sensory profiles' are likely to interact with other aspects of development, such as the effects of rare genetic variants linked to autism (Tabbaa et al., 2023), and contribute to the phenotypic variability seen later in childhood (at the extreme: clinical heterogeneity in autism).