Bridge-building between communities: Imagining the future of biomedical autism research.

A paradigm shift in research culture is required to ease perceived tensions between autistic people and the biomedical research community. As a group of autistic and non-autistic scientists and stakeholders, we contend that through participatory research, we can reject a deficit-based conceptualization of autism while building a shared vision for a neurodiversity-affirmative biomedical research paradigm.

Editorial Perspective: The paradox of precision health in early development - building large samples to yield individual-level measures.

Precision health refers to the use of individualised biomarkers or predictive models to provide more tailored information about an individual's likely prognosis. For child psychiatry and psychology, we argue that this approach requires a focus on neurocognitive measures collected in early life and at large scale. However, the large sample sizes necessary to uncover individual-level predictors are currently rare in studies of neurodevelopmental conditions in early childhood. We recommend two strategies going forward: first, including neurocognitive measures in new national cohort studies, and second, synergising measures and data across currently funded longitudinal studies.

The roles of sensory hyperreactivity and hyporeactivity in understanding infant fearfulness and emerging autistic traits.

BACKGROUND: Existing evidence indicates that atypical sensory reactivity is a core characteristic of autism, and has been linked to both anxiety (and its putative infant precursor of fearfulness) and repetitive behaviours. However, most work has used cross-sectional designs and not considered the differential roles of hyperreactivity and hyporeactivity to sensory inputs, and is thus limited in specificity. METHODS: 161 infants with and without an elevated likelihood of developing autism and attention-deficit hyperactivity disorder (ADHD) were followed from 10 to 36 months of age. Parents rated an infant precursor of later anxiety (fearfulness) using the Infant Behaviour Questionnaire at 10 and 14 months, and the Early Childhood Behavioural Questionnaire at 24 months, and sensory hyperreactivity and hyporeactivity at 10, 14 and 24 months using the Infant Toddler Sensory Profile. Domains of autistic traits (restrictive and repetitive behaviours; RRB, and social communication interaction, SCI) were assessed using the parent-rated Social Responsiveness Scale at 36 months. Cross-lagged models tested (a) paths between fearfulness and hyperreactivity at 10-24 months, and from fearfulness and hyperreactivity to later autism traits, (b) the specificity of hyperreactivity effects by including hyporeactivity as a correlated predictor. RESULTS: Hyperreactivity at 14 months was positively associated with fearfulness at 24 months, and hyperreactivity at 24 months was positively associated with SCI and RRB at 36 months. When hyporeactivity was included in the model, paths between hyperreactivity and fearfulness remained, but paths between hyperreactivity and autistic traits became nonsignificant. CONCLUSIONS: Our findings indicate that alterations in early sensory reactivity may increase the likelihood of showing fearfulness in infancy, and relate to later social interactions and repetitive behaviours, particularly in individuals with a family history of autism or ADHD.

Early development and epilepsy in tuberous sclerosis complex: A prospective longitudinal study.

AIM: To characterize early changes in developmental ability, language, and adaptive behaviour in infants diagnosed with tuberous sclerosis complex (TSC), and determine whether clinical features of epilepsy influence this pathway. METHOD: Prospective, longitudinal data were collected within the Early Development in Tuberous Sclerosis (EDiTS) Study to track development of infants with TSC (n = 32) and typically developing infants (n = 33) between 3 and 24 months of age. Questionnaire and observational measures were used at up to seven timepoints to assess infants' adaptive behaviour, developmental ability, language, and epilepsy. RESULTS: A significant group by age interaction effect showed that infants with TSC had lower adaptive functioning at 18 to 24 months old (intercept = 88.12, slope estimate = -0.82, p < 0.001) and lower developmental ability scores from 10 months old (intercept = 83.33, slope estimate = -1.44, p < 0.001) compared to typically developing infants. Early epilepsy severity was a significant predictor of these emerging developmental (R2 = 0.35, p = 0.004, 95% confidence interval [CI] -0.08 to -0.01) and adaptive behaviour delays (R2 = 0.34, p = 0.004, 95% CI -0.05 to -0.01]). Lower vocabulary production (intercept = -1.25, slope = -0.12, p < 0.001) and comprehension scores (intercept = 2.39, slope estimate = -0.05, p < 0.001) in infants with TSC at 24 months old were not associated with epilepsy severity. INTERPRETATION: Divergence of developmental ability and adaptive functioning skills occur in infants with TSC from 10 and 18 months, respectively. Associations between early epilepsy severity and impaired development supports the importance of early intervention to reduce seizure severity.

The importance of decomposing periodic and aperiodic EEG signals for assessment of brain function in a global context.

Measures of early neuro-cognitive development that are suitable for use in low-resource settings are needed to enable studies of the effects of early adversity on the developing brain in a global context. These measures should have high acquisition rates and good face and construct validity. Here, we investigated the feasibility of a naturalistic electroencephalography (EEG) paradigm in a low-resource context during childhood. Additionally, we examined the sensitivity of periodic and aperiodic EEG metrics to social and non-social stimuli. We recorded simultaneous 20-channel EEG and eye-tracking in 72 children aged 4-12 years (45 females) while they watched videos of women singing nursery rhymes and moving toys, selected to represent familiar childhood experiences. These measures were part of a feasibility study that assessed the feasibility and acceptability of a follow-up data collection of the South African Safe Passage Study, which tracks environmental adversity and brain and cognitive development from before birth up until childhood. We examined whether data quantity and quality varied with child characteristics and the sensitivity of varying EEG metrics (canonical band power in the theta and alpha band and periodic and aperiodic features of the power spectra). We found that children who completed the EEG and eye-tracking assessment were, in general, representative of the full cohort. Data quantity was higher in children with greater visual attention to the stimuli. Out of the tested EEG metrics, periodic measures in the theta frequency range were most sensitive to condition differences, compared to alpha range measures and canonical and aperiodic EEG measures. Our results show that measuring EEG during ecologically valid social and non-social stimuli is feasible in low-resource settings, is feasible for most children, and produces robust indices of social brain function. This work provides preliminary support for testing longitudinal links between social brain function, environmental factors, and emerging behaviors.

Neuroadaptive Bayesian optimisation can allow integrative design spaces at the individual level in the social and behavioural sciences and beyond.

Almaatouq et al. propose an integrative experiment design space combined with large samples for scientific advancement. We argue recent innovative designs combining closed-loop experiment designs and Bayesian optimisation allow for integrative experiments at an individual level during a single session, circumventing the necessity for large samples. This method can be applied across disciplines, including developmental and clinical research.

Processing of social and monetary rewards in autism spectrum disorders.

BACKGROUND: Reward processing has been proposed to underpin the atypical social feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social reward processing in ASD. AIMS: Utilising a large sample, we aimed to assess reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD. METHOD: Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.6 years of age) and 181 typically developing participants (7.6-30.8 years of age). RESULTS: Across social and monetary reward anticipation, whole-brain analyses showed hypoactivation of the right ventral striatum in participants with ASD compared with typically developing participants. Further, region of interest analysis across both reward types yielded ASD-related hypoactivation in both the left and right ventral striatum. Across delivery of social and monetary reward, hyperactivation of the ventral striatum in individuals with ASD did not survive correction for multiple comparisons. Dimensional analyses of autism and attention-deficit hyperactivity disorder (ADHD) scores were not significant. In categorical analyses, post hoc comparisons showed that ASD effects were most pronounced in participants with ASD without co-occurring ADHD. CONCLUSIONS: Our results do not support current theories linking atypical social interaction in ASD to specific alterations in social reward processing. Instead, they point towards a generalised hypoactivity of ventral striatum in ASD during anticipation of both social and monetary rewards. We suggest this indicates attenuated reward seeking in ASD independent of social content and that elevated ADHD symptoms may attenuate altered reward seeking in ASD.

Identifying phenotypic and physiological subgroups of preschoolers with autism spectrum disorder.

BACKGROUND: To understand the emergence of symptoms in autism spectrum disorder (ASD), we need to identify the mechanisms that underpin the development of core social skills. Mounting evidence indicates that young children with later ASD attend less to other people, which could compromise learning opportunities with cascading effects. Passive looking behaviour does not tell us about engagement with visual information, but measures of physiological arousal can provide information on the depth of engagement. In the current study, we use heart rate (HR) and heart rate variability (HRV) to measure engagement with social dynamic stimuli in ASD. METHODS: Sixty-seven preschoolers with ASD and 65 typical developing preschoolers between 2 and 4 years of age participated in a study where HR was measured during viewing of social and non-social videos. Using latent profile analyses, more homogeneous subgroups of children were created based on phenotype and physiology. RESULTS: Preschool-aged children with ASD, regardless of their non-verbal, verbal and social competencies, do not differ in overall HR or HRV compared to TD children. However, the ASD group showed a larger increase in HR (more disengagement) than the TD group to later-presented social stimuli. Phenotypic and physiological profiles showed this was primarily the case for children with below average verbal and non-verbal skills, but not necessarily those with more ASD symptoms. CONCLUSION: Children with ASD, especially a subgroup showing moderate cognitive delays, show an increase in HR to social stimuli over time; this may reflect difficulties re-engaging with social information when attention is waning.

Modeling flexible behavior in childhood to adulthood shows age-dependent learning mechanisms and less optimal learning in autism in each age group.

Flexible behavior is critical for everyday decision-making and has been implicated in restricted, repetitive behaviors (RRB) in autism spectrum disorder (ASD). However, how flexible behavior changes developmentally in ASD remains largely unknown. Here, we used a developmental approach and examined flexible behavior on a probabilistic reversal learning task in 572 children, adolescents, and adults (ASD N = 321; typical development [TD] N = 251). Using computational modeling, we quantified latent variables that index mechanisms underlying perseveration and feedback sensitivity. We then assessed these variables in relation to diagnosis, developmental stage, core autism symptomatology, and associated psychiatric symptoms. Autistic individuals showed on average more perseveration and less feedback sensitivity than TD individuals, and, across cases and controls, older age groups showed more feedback sensitivity than younger age groups. Computational modeling revealed that dominant learning mechanisms underpinning flexible behavior differed across developmental stages and reduced flexible behavior in ASD was driven by less optimal learning on average within each age group. In autistic children, perseverative errors were positively related to anxiety symptoms, and in autistic adults, perseveration (indexed by both task errors and model parameter estimates) was positively related to RRB. These findings provide novel insights into reduced flexible behavior in relation to clinical symptoms in ASD.

Editorial perspective: Leaving the baby in the bathwater in neurodevelopmental research.

Neurodevelopmental conditions are characterised by differences in the way children interact with the people and environments around them. Despite extensive investigation, attempts to uncover the brain mechanisms that underpin neurodevelopmental conditions have yet to yield any translatable insights. We contend that one key reason is that psychologists and cognitive neuroscientists study brain function by taking children away from their environment, into a controlled lab setting. Here, we discuss recent research that has aimed to take a different approach, moving away from experimental control through isolation and stimulus manipulation, and towards approaches that embrace the measurement and targeted interrogation of naturalistic, user-defined and complex, multivariate datasets. We review three worked examples (of stress processing, early activity level in ADHD and social brain development in autism) to illustrate how these new approaches might lead to new conceptual and translatable insights into neurodevelopment.

Infant sleep predicts trajectories of social attention and later autism traits.

BACKGROUND: Children with neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) often experience sleep disturbances, but little is known about when these sleep differences emerge and how they relate to later development. METHODS: We used a prospective longitudinal design in infants with a family history of ASD and/or ADHD to examine infant sleep and its relation to trajectories of attention and later neurodevelopmental disorders. We formed factors of Day and Night Sleep from parent-reported measures (including day/night sleep duration, number of naps in the day, frequency of night awakenings and sleep onset problems). We examined sleep in 164 infants at 5-, 10- and 14-months with/without a first-degree relative with ASD and/or ADHD who underwent a consensus clinical assessment for ASD at age 3. RESULTS: By 14-months, infants with a first-degree relative with ASD (but not ADHD) showed lower Night Sleep scores than infants with no family history of ASD; lower Night Sleep scores in infancy were also associated with a later ASD diagnosis, decreased cognitive ability, increased ASD symptomatology at 3-years, and developing social attention (e.g., looking to faces). We found no such effects with Day Sleep. CONCLUSIONS: Sleep disturbances may be apparent at night from 14-months in infants with a family history of ASD and also those with later ASD, but were not associated with a family history of ADHD. Infant sleep disturbances were also linked to later dimensional variation in cognitive and social skills across the cohort. Night Sleep and Social Attention were interrelated over the first 2 years of life, suggesting that this may be one mechanism through which sleep quality influences neurodevelopment. Interventions targeted towards supporting families with their infant's sleep problems may be useful in this population.

Vocalization and physiological hyperarousal in infant-caregiver dyads where the caregiver has elevated anxiety.

Co-regulation of physiological arousal within the caregiver-child dyad precedes later self-regulation within the individual. Despite the importance of unimpaired self-regulatory development for later adjustment outcomes, little is understood about how early co-regulatory processes can become dysregulated during early life. Aspects of caregiver behavior, such as patterns of anxious speech, may be one factor influencing infant arousal dysregulation. To address this, we made day-long, naturalistic biobehavioral recordings in home settings in caregiver-infant dyads using wearable autonomic devices and miniature microphones. We examined the association between arousal, vocalization intensity, and caregiver anxiety. We found that moments of high physiological arousal in infants were more likely to be accompanied by high caregiver arousal when caregivers had high self-reported trait anxiety. Anxious caregivers were also more likely to vocalize intensely at states of high arousal and produce intense vocalizations that occurred in clusters. High-intensity vocalizations were associated with more sustained increases in autonomic arousal for both anxious caregivers and their infants. Findings indicate that caregiver vocal behavior differs in anxious parents, cooccurs with dyadic arousal dysregulation, and could contribute to physiological arousal transmission. Implications for caregiver vocalization as an intervention target are discussed.

Alexithymia in autism: cross-sectional and longitudinal associations with social-communication difficulties, anxiety and depression symptoms.

BACKGROUND: Alexithymia (difficulties in identifying and describing emotion) is a transdiagnostic trait implicated in social-emotional and mental health problems in the general population. Many autistic individuals experience significant social-communication difficulties and elevated anxiety/depression and alexithymia. Nevertheless, the role of alexithymia in explaining individual variability in the quality/severity of social-communication difficulties and/or anxiety and depression symptoms in autism remains poorly understood. METHODS: In total, 337 adolescents and adults (autism N = 179) were assessed for alexithymia on the Toronto Alexithymia Scale and for social-communication difficulties, anxiety and depression symptoms. A total of 135 individuals (autism N = 76) were followed up 12-24 months later. We used regression models to establish cross-sectional and longitudinal associations between alexithymia, social-communication difficulties, anxiety and depression symptoms. RESULTS: Autistic individuals reported significantly higher alexithymia than comparison individuals (p < 0.001, r effect size = 0.48), with 47.3% of autistic females and 21.0% of autistic males meeting cut-off for clinically relevant alexithymia (score ⩾61). Difficulties in describing feelings were particularly associated with current self-reported social-communication difficulties [p < 0.001, ß = 0.57, 95% confidence interval (CI) 0.44-0.67] and predicted later social-communication difficulties (p = 0.02, ß = 0.43, 95% CI 0.07-0.82). Difficulties in identifying feelings were particularly associated with current anxiety symptom severity (p < 0.001, ß = 0.54, 95% CI 0.41-0.77) and predicted later anxiety (p = 0.01; ß = 0.31, 95% CI 0.08-0.62). CONCLUSIONS: Our findings suggest that difficulties in identifying v. describing emotion are associated with differential clinical outcomes in autism. Psychological therapies targeting emotional awareness may improve social-communication and anxiety symptoms in autism, potentially conferring long-term benefits.

Altered theta-beta ratio in infancy associates with family history of ADHD and later ADHD-relevant temperamental traits.

BACKGROUND: Uncovering the neural mechanisms that underlie symptoms of attention deficit hyperactivity disorder (ADHD) requires studying brain development prior to the emergence of behavioural difficulties. One new approach to this is prospective studies of infants with an elevated likelihood of developing ADHD. METHODS: We used a prospective design to examine an oscillatory electroencephalography profile that has been widely studied in both children and adults with ADHD - the balance between lower and higher frequencies operationalised as the theta-beta ratio (TBR). In the present study, we examined TBR in 136 10-month-old infants (72 male and 64 female) with/without an elevated likelihood of developing ADHD and/or a comparison disorder (Autism Spectrum Disorder; ASD). RESULTS: Infants with a first-degree relative with ADHD demonstrated lower TBR than infants without a first-degree relative with ADHD. Further, lower TBR at 10 months was positively associated with temperament dimensions conceptually related to ADHD at 2 years. TBR was not altered in infants with a family history of ASD. CONCLUSIONS: This is the first demonstration that alterations in TBR are present prior to behavioural symptoms of ADHD. However, these alterations manifest differently than those sometimes observed in older children with an ADHD diagnosis. Importantly, altered TBR was not seen in infants at elevated likelihood of developing ASD, suggesting a degree of specificity to ADHD. Taken together, these findings demonstrate that there are brain changes associated with a family history of ADHD observable in the first year of life.

Unique dynamic profiles of social attention in autistic females.

BACKGROUND: Social attention affords learning opportunities across development and may contribute to individual differences in developmental trajectories, such as between male and female individuals, and in neurodevelopmental conditions, such as autism. METHODS: Using eye-tracking, we measured social attention in a large cohort of autistic (n = 123) and nonautistic females (n = 107), and autistic (n = 330) and nonautistic males (n = 204), aged 6-30 years. Using mixed Growth Curve Analysis, we modelled sex and diagnostic effects on the temporal dynamics of proportional looking time to three types of social stimuli (lean-static, naturalistic-static, and naturalistic-dynamic) and examined the link between individual differences and dimensional social and nonsocial autistic traits in autistic females and males. RESULTS: In the lean-static stimulus, average face-looking was higher in females than in males of both autistic and nonautistic groups. Differences in the dynamic pattern of face-looking were seen in autistic vs. nonautistic females, but not males, with face-looking peaking later in the trial in autistic females. In the naturalistic-dynamic stimulus, average face-looking was higher in females than in males of both groups; changes in the dynamic pattern of face looking were seen in autistic vs. nonautistic males, but not in females, with a steeper peak in nonautistic males. Lower average face-looking was associated with higher observer-measured autistic characteristics in autistic females, but not in males. CONCLUSIONS: Overall, we found stronger social attention in females to a similar degree in both autistic and nonautistic groups. Nonetheless, the dynamic profiles of social attention differed in different ways in autistic females and males compared to their nonautistic peers, and autistic traits predicted trends of average face-looking in autistic females. These findings support the role of social attention in the emergence of sex-related differences in autistic characteristics, suggesting an avenue to phenotypic stratification.

Habitual night waking associates with dynamics of waking cortical theta power in infancy.

The implications of the substantial individual differences in infant sleep for early brain development remain unclear. Here, we examined whether night sleep quality relates to daytime brain activity, operationalized through measures of EEG theta power and its dynamic modulation, which have been previously linked to later cognitive development. For this longitudinal study, 76 typically developing infants were studied (age: 4-14 months, 166 individual study visits) over the course of 6 months with one, two, three, or four lab visits. Habitual sleep was measured with a 7-day sleep diary and actigraphy, and the Brief Infant Sleep Questionnaire. Twenty-channel EEG was recorded while infants watched multiple rounds of videos of women singing nursery rhymes; oscillatory power in the theta band was extracted. Key metrics were average theta across stimuli and the slope of change in theta within the first novel movie. Both objective and subjective sleep assessment methods showed a relationship between more night waking and higher overall theta power and reduced dynamic modulation of theta over the course of the novel video stimuli. These results may indicate altered learning and consolidation in infants with more disrupted night sleep, which may have implications for cognitive development.

Inhibitory control and problem solving in early childhood: Exploring the burdens and benefits of high self-control.

Low inhibitory control (IC) is sometimes associated with enhanced problem-solving amongst adults, yet for young children high IC is primarily framed as inherently better than low IC. Here, we explore associations between IC and performance on a novel problem-solving task, amongst 102 English 2- and 3-year-olds (Study 1) and 84 Swedish children, seen at 18-months and 4-years (Study 2). Generativity during problem-solving was negatively associated with IC, as measured by prohibition-compliance (Study 1, both ages, Study 2 longitudinally from 18-months). High parent-reported IC was associated with poorer overall problem-solving success, and greater perseveration (Study 1, 3-year-olds only). Benefits of high parent-reported IC on persistence could be accounted for by developmental level. No concurrent association was observed between problem-solving performance and IC as measured with a Delay-of-Gratification task (Study 2, concurrent associations at 4-years). We suggest that, for young children, high IC may confer burden on insight- and analytic-aspects of problem-solving.

Annual Research Review: Anterior Modifiers in the Emergence of Neurodevelopmental Disorders (AMEND)-a systems neuroscience approach to common developmental disorders.

We present the Anterior Modifiers in the Emergence of Neurodevelopmental Disorders (AMEND) framework, designed to reframe the field of prospective studies of neurodevelopmental disorders. In AMEND we propose conceptual, statistical and methodological approaches to separating markers of early-stage perturbations from later developmental modifiers. We describe the evidence for, and features of, these interacting components before outlining analytical approaches to studying how different profiles of early perturbations and later modifiers interact to produce phenotypic outcomes. We suggest this approach could both advance our theoretical understanding and clinical approach to the emergence of developmental psychopathology in early childhood.

Ethical dimensions of translational developmental neuroscience research in autism.

BACKGROUND: Since the 1990s, increasing research has been devoted to the identification of biomarkers for autism to help attain more objective diagnosis; enable early prediction of prognosis; and guide individualized intervention options. Early studies focused on the identification of genetic variants associated with autism, but more recently, research has expanded to investigate neurodevelopmental markers. While ethicists have extensively discussed issues around advances in autism genomics, much less ethical scrutiny has focused on research on early neurodevelopment and on the interventions being developed as a result. OBJECTIVES: We summarize the current state of the science on the identification of early markers for autism and its potential clinical applications, before providing an overview of the ethical issues arising from increasing understanding of children's neurodevelopment in very early life. RESULTS: Advances in the understanding of brain and behavioral trajectories preceding later autism diagnosis raise ethical concerns around three themes: (a) New models for understanding autism; (b) Risks and benefits of early identification and intervention; and (c) Communication of early concerns to families. These ethical issues should be further investigated in research conducted in partnership with autistic people and their families. CONCLUSIONS: This paper highlights the need for ethical scrutiny of early neurodevelopmental research in autism. Scrutiny requires expertise and methods from the basic sciences and bioethics, as well as constructive collaborations among autistic people, their parents, and autism researchers to anticipate early interventions that serve the community's interests and accommodate the varied experiences and preferences of people on the spectrum and their families.

Development of the pupillary light reflex from 9 to 24 months: association with common autism spectrum disorder (ASD) genetic liability and 3-year ASD diagnosis.

BACKGROUND: Although autism spectrum disorder (ASD) is heritable, the mechanisms through which genes contribute to symptom emergence remain unclear. Investigating candidate intermediate phenotypes such as the pupillary light reflex (PLR) prospectively from early in development could bridge genotype and behavioural phenotype. METHODS: Using eye tracking, we longitudinally measured the PLR at 9, 14 and 24 months in a sample of infants (N = 264) enriched for a family history of ASD; 27 infants received an ASD diagnosis at 3 years. We examined the 9- to 24-month developmental trajectories of PLR constriction latency (onset; ms) and amplitude (%) and explored their relation to categorical 3-year ASD outcome, polygenic liability for ASD and dimensional 3-year social affect (SA) and repetitive/restrictive behaviour (RRB) traits. Polygenic scores for ASD (PGSASD ) were calculated for 190 infants. RESULTS: While infants showed a decrease in latency between 9 and 14 months, higher PGSASD was associated with a smaller decrease in latency in the first year (ß = -.16, 95% CI = -0.31, -0.002); infants with later ASD showed a significantly steeper decrease in latency (a putative 'catch-up') between 14 and 24 months relative to those with other outcomes (typical: ß = .54, 95% CI = 0.08, 0.99; other: ß = .53, 95% CI = 0.02, 1.04). Latency development did not associate with later dimensional variation in ASD-related traits. In contrast, change in amplitude was not related to categorical ASD or genetics, but decreasing 9- to 14-month amplitude was associated with higher SA (ß = .08, 95% CI = 0.01, 0.14) and RRB (ß = .05, 95% CI = 0.004, 0.11) traits. CONCLUSIONS: These findings corroborate PLR development as possible intermediate phenotypes being linked to both genetic liability and phenotypic outcomes. Future work should incorporate alternative measures (e.g. functionally informed structural and genetic measures) to test whether distinct neural mechanisms underpin PLR alterations.