Many autistic people have challenges with adaptive function, impacting education, employment and independent-living goals. Adaptive function outcomes of autistic people vary considerably, which makes planning for future needs challenging. Here, using a developmentally sensitive approach, we investigated if cortico-cortical functional connectivity – a core neurobiological feature that differs in autism – could predict longitudinal changes in adaptive function in autistic people. Using electroencephalography in 150 autistic and 159 non-autistic participants aged 6–31 years, we investigated if mean degree and network organisation (small-world index) predict longitudinal changes in adaptive function over 19-months. We found that small-world index significantly predicted changes in adaptive function in autistic people across the entire age-range. Predictive performance was best for autistic youth (15–24-year-olds), where mean degree and small-world index explained 21 and 30% of additional variance in outcomes, respectively, outperforming measures of intelligence and autistic features. In categorising binary (improved versus not-improved) outcomes, the model containing mean degree had an AUC of 0.84 [95% CI: 0.71–0.97] in 15–24-year-olds, while that containing small-world index had an AUC of 0.76 [95% CI: 0.63–0.89] across the 6–31-year age-range. Both metrics demonstrated properties desired in prognostic biomarkers: high test-retest reliability and convergence with underlying biology (significant associations with genetic variation in brain volume-related genes). Thus, we demonstrate the first evidence that electroencephalography-derived functional connectivity metrics show promise as prognostic biomarkers of adaptive function in autistic people. Potential precision-medicine applications include stratifying participants in clinical trials and identifying those at risk of declining function in clinical settings.

Sleep difficulties represent a health priority for autistic adults, yet scalable real-world sleep measurement tools remain limited. Remote measurement technologies (RMT), including wearable and smartphone data, offer low‑burden approaches but feasibility in autistic populations is unclear. We evaluated a 28-day protocol combining passive Fitbit sleep staging and smartphone sensor data, and active daily sleep quality ratings in autistic (n = 34) and nonautistic (n = 39) participants (14–35 years). Median data availability was over 70% across modalities. However, usable data (days with valid sleep period and quality rating) were lower (< 60%), particularly for autistic participants, whose tactile sensitivity associated with reduced usable Fitbit data. Autistic participants reported lower sleep quality; however, few differences in passively derived sleep features emerged. Several features (e.g., sleep efficiency, duration, REM proportion) were related to subjective sleep quality, as were passively-derived sleep profile clusters. This study provides foundational work for developing RMT suitable for sleep measurement in autistic populations.

Background Autism is characterized by social-communicative difficulties, with sex differences in symptom presentation. Social functioning is inherently dynamic, however, many neuroimaging studies rely on static, time-averaged approaches that obscure time-varying network interactions, potentially limiting our ability to capture the dynamic processes underlying social cognition. The fusiform gyrus (FFG), central to face and social perception, shows differences in functional connectivity in autism, yet is rarely examined dynamically or as a spatially heterogeneous structure. Here, we investigate the dynamic functional connectivity of FFG subregions in terms of their large-scale network configurations as a function of diagnosis and sex. Methods We applied micro co-activation patterns analysis (μCAPs) to resting-state fMRI data from 286 autistic individuals (208:78 males:females) and 228 non-autistic individuals (146:82 males:females), aged 6-30 years, from the EU-AIMS LEAP dataset. μCAPs were identified using k-means clustering with FFG as the seed, and connectopic mapping positioned each μCAP along the principal connectivity gradient. We quantified μCAPs occurrence and further examined dwell time, transition probabilities, and spatial extent, along with associations with social functioning. Results Six μCAPs mapped onto distinct FFG subregions along a posterior-anterior axis. A significant sex-by-diagnosis interaction emerged for a default mode network (DMN)-related μCAP. Non-autistic females exhibited significantly more frequent occurrences, longer dwell times and distinct transition dynamics compared to males, while no sex difference was observed in autism. The spatial extent of this μCAP showed a reversal of typical sex effects. Conclusions Autism is associated with an attenuation and reversal of typical sex differences in the functional configuration and spatial extent of FFG-DMN coupling, indicating that neural signatures of social-cognitive functions are sex-specific and dynamic. These findings suggest that sex is a neurobiologically meaningful dimension of heterogeneity in autism, expressed in dynamic network organization.

The excitatory/inhibitory (E/I) imbalance theory suggests that excitatory and inhibitory alterations underlies autism characteristics. However, genetic underpinnings of this imbalance and its impact on brain function and behavior remains unclear. We explored causal links between glutamate and GABA gene-set polygenic scores (PGS) for autism and core autism characteristics, putting particular attention on the restricted- and repetitive behaviors (RRBs) domain by including functional activity (fMRI) during inhibitory control (in the anterior cingulate cortex (ACC) and striatum). Causal links between genes, brain and behavior was evaluated using Bayesian Constraint-based Causal Discovery (BCCD) algorithms, to build causal models of these relationships in a discovery sample (LEAP cohort: autistic = 343, neurotypical = 253) and two generalization cohorts with partially overlapping measures (TACTICS cohort: autistic = 60, neurotypical = 100, Simon Simplex Collection: autistic = 2756). In the discovery sample, we found a causal link between glutamate PGS and core clinical characteristics of autism, particularly the communication domain (Autism Diagnostic Interview-Revised) in autistic participants, with 95% reliability. We did not find links between functional activity during inhibitory control and other measures. For one generalization cohort, we further report on the impact of 1H-MRS measures of glutamate, identifying a causal link between GABA autism PGS on ACC glutamate concentrations. Not all links were identified in the generalization cohorts, which may be due to clinical and genetic differences between the cohorts. While our results reinforce the previously found association between glutamate genes and core clinical autism behaviors, task-based functional activity may not be causally related to RRBs.

Background Autism frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD), which significantly impacts developmental outcomes and quality of life. While executive functions (EF) and reward processing differences are commonly observed in both conditions, it remains unclear whether early neurocognitive variation can predict emergence of ADHD traits in preschool children. This study aimed to identify transdiagnostic neurocognitive profiles in a preschool sample and evaluate their clinical, neurobiological, and prognostic relevance. Method This study utilised data from a well-characterised cohort of 240 autistic and neurotypical preschoolers aged 34–52 months. Indices from a novel touchscreen battery assessing inhibitory control, sustained attention, and reward learning were entered into a density-based clustering algorithm. The resulting subgroups were externally characterised on concurrent clinical and neuroanatomical characteristics, and as predictors of ADHD features after 12–15 months. Results The clustering analysis identified four neurocognitive subgroups: EF+Reward difficulties, showing challenges across all assessed domains alongside elevated autistic and ADHD traits but typical-range IQ; Low Completion, marked by task completion difficulties, lower IQ, and moderate ADHD traits; and two subgroups with relatively intact profiles, exhibiting typical neurocognitive performance and low ADHD traits. The EF+Reward difficulties and Low Completion subgroups showed widespread reductions in frontal and parietal cortical surface area relative to the intact groups. Subgroup membership also predicted ADHD traits over time, supporting the prognostic value of these neurocognitive profiles. Limitations: External replication was not possible due to the absence of comparable publicly available preschool cohorts. Multiple internal and external validation strategies nonetheless support subgroup robustness. Additional limitations include reliance on parent-reported ADHD measures and a small EF+Reward difficulties subgroup. Conclusions Neurocognitive subtypes, derived from scalable innovative tools, can parse heterogeneity in early development in autistic and neurotypical sample and predict early ADHD features, mapping onto relevant neuroanatomy. Our study highlights the potential of early transdiagnostic cognitive profiling for identifying children at an increased likelihood of co-occurring autistic and ADHD traits and informing targeted early interventions.

Abstract Sensory processing differences are a core feature of autism, affecting 60–95% of individuals, yet the associated neural mechanisms remain unclear. An excitation–inhibition (E/I) imbalance in brain circuits has been proposed, but in vivo evidence linking genetic variation in E/I pathways, regional neurochemistry, neural circuit function, and sensory behaviour has been lacking. Here we performed a multimodal investigation in 206 individuals (130 autistic), integrating gene-set polygenic scores for excitatory glutamatergic and inhibitory gamma-aminobutyric acid (GABA)-ergic pathways, magnetic resonance spectroscopy (MRS) measures of regional GABA and Glx (glutamate + glutamine) levels, vibrotactile psychophysical measures of tactile perception, and questionnaire measures of behavioural sensory reactivity. We found that glutamatergic polygenic scores predicted thalamic glutamate levels in neurotypical but not autistic individuals, suggesting altered genotype–neurochemistry coupling in autism. Thalamic Glx:GABA levels associated with tactile perception in both groups, but with opposing directions of effect, indicating that autistic and neurotypical individuals achieve similar perceptual outcomes with potentially differing thalamocortical circuit mechanisms. Within autistic individuals, tactile perceptual differences further related to behavioural sensory reactivity. Together, these findings suggest that autistic sensory processing potentially relies on distinct circuit mechanisms linking genetic variation, neurochemistry and perception. This work thus has important implications for how sensory differences are conceptualised, studied, and interpreted, and ultimately for how interventions and support are developed. Abstract Figure Summary Figure Summary of our comprehensive investigation of the role of excitation and inhibition in sensory processing differences in autism by integrating GABA and glutamate gene set polygenic scores (PGS), MRS-measured thalamic and anterior cingulate cortex (ACC) Glx (glutamate + glutamine) and GABA+ (GABA + macromolecules) levels, vibrotactile psychophysical measures of tactile perception (tactile detection thresholds, discrimination thresholds and tactile adaptation etc.) and questionnaire-based measures of sensory reactivity (behavioural and emotional responses to sensory stimuli, including hyper-and hypo-reactivity).

Behavioural, structural, and functional neuroimaging differences exist between individuals with antisocial personality disorder with (ASPD + P) or without psychopathy (ASPD-P). However, the aetiological mechanisms underpinning such differences remain unclear, hindering treatment development. Intranasal oxytocin (OT) has shown modulatory effects on social brain function in healthy and antisocial populations. We investigated the effects of OT on resting-state brain function in individuals with violent offending histories with ASPD+/-P using arterial spin labelling to measure regional cerebral blood flow (rCBF). A double-blind, placebo-controlled, crossover design was employed with males with ASPD (ASPD + P: N = 17, ASPD-P: N = 14) and healthy male non-offenders (N = 22). Both ASPD subtypes exhibited reduced rCBF in frontotemporal regions compared to non-offenders. Individuals with ASPD + P showed significantly greater rCBF increases in posterior default mode network regions compared to individuals with ASPD-P. OT administration selectively decreased rCBF in the left basal ganglia of the ASPD-P group, an effect not observed in ASPD + P or non-offender groups. These findings highlight functional brain differences between individuals with ASPD + P and ASPD-P at rest and demonstrate oxytocin’s differential impact on resting-state measures. Further understanding of the origins of these neurobiological differences could inform targeted therapeutic strategies for individuals with ASPD with and without psychopathy.

Autism is hypothesised to have prenatal origins, but direct evidence from very early life neuroimaging is limited. We conducted a prospective, longitudinal brain MRI study of 103 children, imaged at least once at fetal, neonatal and/or infant (6 month) timepoints, and quantified autistic traits at 3 years of age using the Autism Diagnostic Observation Schedule-2 (ADOS-2). This cohort was enriched with 17 children with a 1st degree relative with autism and/or ADHD to increase the likelihood that measurable autistic traits would be observed. We report that children with higher autistic traits at 3 years (n = 25) had significantly larger lateral ventricles at each of the prenatal and early postnatal timepoints with data available, compared to those with lower autistic traits. At the neonatal timepoint, cortical enlargement accompanied larger ventricles. These relationships remained significant when non-specific early learning outcomes were controlled for using the Mullen Scales of Early Learning. In secondary analyses, children who met DSM-5 criteria for autism at 3 years also showed larger-than-expected lateral ventricular size when all fetal, neonatal and infant scans were modelled jointly. The relationship between ventricular size at 6 months of age and ADOS-2 autistic traits at 3 years was replicated in an independent cohort of 38 children, supporting the robustness of this association. These findings provide the earliest longitudinal evidence that enlargement of the lateral ventricles associated with higher autistic traits is detectable from fetal life and emphasise prenatal developmental origins which precede postnatal influences on outcomes.

Congenital heart disease (CHD) occurs in over half of individuals with 22q11.2 deletion syndrome (22q11.2DS), but lesion type varies widely. We analyzed 3,016 unrelated postnatal individuals with 22q11.2DS from specialized centers in the United States, Canada, Europe, South America, Israel, and Australia, including 1,868 with whole-genome sequencing. The typical 3 Mb LCR22 A-D deletion was present in 2,788 individuals (92.4%), with smaller A-B (n=172, 5.7%) and A-C (n=56, 1.9%) deletions comprising the remaining cohort. In multivariable mixed-effects logistic regression adjusting for sex, deletion group, genome-wide principal components (PCs), and recruitment site, four non-intercept associations, to test relationships, met study-wide FDR statistical significance. Compared with the A-B deletion, the A-D deletion was associated with lower odds of persistent truncus arteriosus (OR=0.37, 95% CI 0.18-0.75) and higher odds of isolated septal defects (OR=4.68, 95% CI 1.71-12.83), although precision was limited by the smaller A-B group. PC2 was associated with lower odds of pulmonary stenosis/atresia with additional lesions (OR=0.73, 95% CI 0.61-0.87), and PC4 with higher odds of abnormal origin of the subclavian arteries (OR=2.59, 95% CI 1.37-4.89). ADMIXTURE-derived continental ancestry proportions did not show independent associations with these two PC-associated outcomes. These lesion-specific findings suggest the hypothesis that deletion interval and broader genetic background may contribute to CHD variability in 22q11.2DS, pending future replication. KEY MESSAGES:What is already known on this topic: Chromosome 22q11.2DS is a rare genetic disorder associated with serious medical challenges. Most affected individuals have congenital heart disease but with variable phenotypic expression. One of the main questions still an open topic in the field is why individuals with 22q11.2DS show extensive phenotypic heterogeneity.What this study adds: Analysis of retrospective data on 3,016 individuals with 22q11.2DS and 1,868 with sequence data suggest that deletion type and genetic variation influence phenotypic expression of congenital heart disease.How this study might affect research, practice or policy: This work informs the clinician as to the importance of testing for deletion type and obtaining accurate cardiac phenotypes to diagnose 22q11.2DS that will improve the prognosis and disease progression. It also implicates the complexity of sex and ancestry as confounding factors that will help guide future research studies to identify genetic modifiers of congenital heart disease.

Background The field of biomedical research is entering a new era, in which public data sharing is increasingly the norm. There are many advantages of embracing data sharing initiatives, including tackling the replication crisis through enhanced transparency and publication of null findings, facilitating global collaborations to accelerate research progress, enhancing cost-effectiveness by reducing duplication of efforts, and making scientific advances more accessible to the public. However, there are also several crucial ethical and logistical challenges that must be addressed to maximise the benefits of data sharing and minimise risks. The potential, and increasingly recognised, risks of unregulated data sharing (e.g., data reidentification, misuse, and lack of representativeness due to variability in who agrees to share data) have also been exemplified by high profile data breaches and directly clash with efforts to make research more robust, accessible, and global. Methods/Results Here, we narratively outline current challenges for data sharing from the perspective of child and adolescent psychiatry, one area where they may be particularly acute. For example, child and early adolescent research often requires caregivers to consent on behalf of a minor – increasing the responsibility of researchers to consider how the science of today may evolve into the future (when those individuals are no longer minors). We use data from our research consortium Autism Innovative Medicines Study - 2 - Trials (AIMS-2-TRIALS; https://www.aims-2-trials.eu/) to illustrate the points raised in this perspective piece. Conclusions We also propose some potential solutions to begin to address current challenges for data sharing, focusing on key priorities, including shared control of data curation between researcher and participant communities and equity of access by research groups to the tools and resources needed to conduct responsible and sustainable data sharing.

Stimulants, such as methylphenidate (MPH), are beneficial for attention-deficit/hyperactivity disorder (ADHD), but individual response varies. A deeper understanding of the mechanisms underpinning response is needed. Previous studies suggest that a single MPH dose modulates resting-state functional connectivity (rs-fc). We investigated whether single-dose induced rs-fc changes were associated with post-dose optimization clinical response. Fifty-six adults with ADHD underwent rs-functional magnetic resonance imaging (rs-fMRI) under placebo and a single MPH dose, before starting MPH treatment. Clinical response was measured at two months. We tested if a single MPH dose (vs. placebo) shifted rs-fc; how these shifts were associated with treatment response (categorical approach); and whether these associations were driven by improvement on either ADHD symptom domain. A single MPH dose (vs. placebo) increased rs-fc in three subcortical-cortical and cerebellar-cortical clusters. Enhanced rs-fc between the cerebellar vermis (lobule 6) and the left precentral gyrus was associated with a greater probability of responding to treatment (χ2(7) = 22.740, p = .002) and with an improvement on both inattentive and hyperactive/impulsive symptoms (both p ≤ .001). We provide proof-of-concept that the brain functional response to a single MPH dose, administered before starting routine treatment, is indicative of two-month clinical response in adult ADHD. This may encourage future replication using clinically applicable measures.

Abstract Background Autism, a highly heritable psychiatric condition, is hypothesised believed to be associated with altered synaptic structure and function, as indicated by findings from genetic, post-mortem, and pre-clinical studies. Aims & Objectives In this study, we used positron emission tomography (PET) to investigate synaptic density in vivo. Utilizing a twin design, our objective was to isolate autism specific variation. Methods We examined seven twin pairs discordant for autism (aged 22-29; three male, two female, and two mixex pairs; five monozygotic, two dizygotic pairs; five qualitatively, two quantitatively discordant pairs), alongside eight independent controls (aged 20-27). Radioligand [11 C]UCB-J binds to synaptic vesicle 2A (SV2A). To estimate synaptic density, we employed volume of distribution (VT) using radioactivity measured in blood and binding potential (BPND) with SV2A devoid centrum semi-ovale (CSO) as reference region. To compare the twin pairs, we conducted paired t-tests; for the entire sample, we ran generalized estimating equation (GEE) models. Results Neither the t-tests nor the GEE models revealed statistically significant differences in synaptic density between autistic twins and their co-twins. While we observed lower synaptic density in autistic twins compared to controls in some brain regions using BPND, no significant differences were observed using VT. Although not statistically significant, we did observe group differences in VT of CSO (which served as the reference region). Discussion & Conclusion We did not find any differences in synaptic density between autistic twins and their non-autistic (or less autistic) co-twins. The intra-pair similarities imply that although synaptic density is highly heritable, it may reflect genetic liability for autism, rather than being associated with an autistic phenotype display. We did not find any differences in VT between groups, whereas our collaborators did observe lower mean VT in the autistic group, compared to controls (preliminary findings, presented as a poster, not published). When modelling synaptic density with CSO as a reference region, differences in BPND were found between autistic twins and non-autistic controls. Noteworthy, this analysis rests on the premise that there should be no discrepancies in the reference region between the groups. However, this assumption is contravened by the presence of the observed distinctions in CSO VT between the groups, as well as documented variations in white matter within autistic brains4. Consequently, it is plausible that the observed differences in BPND do not directly relate to differences in synaptic density, but rather reflect variations in white matter composition (and thus the behaviour of the radiotracer within the CSO). This consideration underscores the importance of cautious interpretation of results and accounting for potential confounders when interpreting differences in synaptic density. References 1. Tang et al. Neuron (2014) 2. Bagni et al. Neuron (2019) 3. Bourgeron et al. Nature Reviews Neuroscience (2015) 4. Faraji et al. Pscyhiatry Research: Neuroimaging (2023)

Background Research priorities for autistic people include developing effective interventions for the numerous challenges affecting their daily living, for example, mental health problems, sleep difficulties, and social well-being. However, clinical research progress is limited by a lack of validated objective measures that represent target outcomes for improvement. Digital technologies, including wearable devices and smartphone apps, provide opportunities to develop novel measures that may reflect everyday experience and complement key clinical assessments. However, little is known about the acceptability and feasibility of implementing digital data collection in this population. Objective The primary objective of this study is to evaluate the usability, acceptability, adherence, and feasibility of a dual in-person and remote (ie, at-home) protocol. Secondarily, we aim to explore the properties of certain resulting data with a view to developing novel digital end points for key target outcomes, including social communication, sleep, and mental health. Methods Eligible autistic and nonautistic in the AIMS Longitudinal European Autism Project were invited to participate in a digitally augmented in-person Autism Diagnostic Observation Schedule-2 (ADOS-2) and a 28-day remote measurement (RM) protocol involving wearing a Fitbit device, downloading a passive smartphone data collection app, and using 2 active reporting apps. Results The first AIMS Longitudinal European Autism Project study participants were enrolled in September 2021 (in-person component) and March 2022 (RM component). To date, 190 participants have taken part in the digitally augmented ADOS-2 component, and 86 participants have been enrolled for the RM protocol. Recruitment is now complete with some RM data collection ongoing until August 2025. Data analysis has commenced, including qualitative framework analysis of feedback interview data coproduced with autism community members, exploration of acceptability and feasibility metrics, pipeline development for ADOS-2 speech analysis, and RM sleep measures. Conclusions This study lays important groundwork in understanding the acceptability and feasibility of in-person and remotely implemented digital measurement procedures to capture meaningful outcomes in domains important to improving everyday life for autistic people. International Registered Report Identifier (IRRID) DERR1-10.2196/71145

Background Vitamin D is increasingly recognised as a key contributor to brain development and neuroimmune regulation, as evidenced by numerous studies linking pre- and postnatal variability in vitamin D levels to a range of neurodevelopmental conditions (autism, attention deficit hyperactivity disorders). Despite this growing body of evidence, the precise neurobiological mechanisms through which vitamin D exerts its effects remain unclear, limiting our understanding of how it may shape neurodevelopmental trajectories. In this context, examining genetic variants involved in vitamin D signalling offers a powerful avenue to uncover its role in the developing brain. By tracing the influence of these genetic markers, we can move beyond observational associations to explore how vitamin D contributes to neural maturation, sensory processing, and broader neurobiological homeostasis. Methods We leverage the genome-wide association summary statistics for vitamin D levels, measured in the UK Biobank and explored i) the genome-wide and local association between vitamin D-associated markers and common genetic variants influencing autism risk, based on the PGC-ASD GWAS; and ii) the enrichment of vitamin D-related genetic markers across candidate autism genes curated by the SFARI consortium; iii) the biological function and pattern of brain expression of vitamin D- genetic markers with a neurodevelopmental link.Next, we leverage a deeply-phenotyped clinical sample of ∼ 400 autistic and neurotypical individuals (AIMS-2 TRAILS - LEAP) and explored how individual load of vitaminD-related genetic markers, in the form of a polygenic score, linked clinical features of autism, neuroanatomy and neurometabolic responses using combined MRI and PET data. Results First, we reported a global correlation between vitamin D-level- variability and ASD (p =.04), with four genomic loci retaining bivariate association signal. Using the candidate gene approach, we reported a significant association between vitamin D genetics and autism SFARI genes (p=.0003). Functional assessment of vitamin D-autism shared genetics supports their role in lipid biosynthesis, synaptic signalling and immune-metabolic pathways, with peaks of expression in tempo-parietal and occipital cortical regions and in subcortex.Using the polygenic score approach, we registered marginal differences in vitaminD-PGS between people with and without a confirmed autism diagnosis (p = .01). Looking at individual autistic traits, vitamin D-PGS was consistently associated with sensory traits (p = .004-.0005), but not other autistic traits. Also, vitamin D-PGS was associated with neuroanatomical differences in somatosensory areas. Building on this evidence, we explored vitamin D genetics influence on PET-derived neurometabolic responses in key sensory hubs (thalamus). We identified significant association between vitaminD-pgs and choline, glutathione, lipids profile (p < .0001). Discussion Our study provides novel insights on the neurobiological role of vitamin D. Our findings suggest that vitamin D genetics may influence neurodevelopment by influencing neurometabolism, lipid synthesis - and possible influence on synaptic transmission and inflammation. Our results also point towards a role of vitamin D in sensory processing, with an enrichment of vitamin D genes in sensory areas further confirmed by individual-level association of vitamin D genetics and sensory traits and metabolic responses in key sensory regions of the brain.

Neural populations synchronise their activity with either zero-phase delay (activity in interacting regions occurs simultaneously) or a phase delay (activity in one region follows the other). In electroencephalography and magnetoencephalography functional connectivity analyses, artefactual connectivity can also occur with zero-phase delay. To minimise artefact, contemporary analyses typically exclude all zero-phase-delay interactions. However, the extent to which "true" interactions are resultingly lost-and the impact this has on the performance of functional connectivity metrics as biomarkers-remains unknown. Here, we show that most cortico-cortical functional connectivity occurs with zero- or near-zero phase delay, even where such connectivity is unlikely to be artefactual. Including, rather than excluding, zero-phase-delay connectivity increases the reliability, convergence with neurobiology (structure-function concordance, homotopic interhemispheric connectivity, and age-related connectivity changes), and prognostic ability of functional connectivity metrics. We find that excluding zero-phase-delay connections penalises functional connectivity strength between the strongest structurally connected regions: stronger structural connections lead to functional connections with phase delays closer to zero, mediated by a shorter signal propagation time. Our findings challenge generally accepted assumptions that zero-phase-exclusive methods are superior to zero-phase-inclusive methods.

Abstract Background Functionally inter-connected large-scale brain networks underpin complex human behaviour and a wide range of alterations in this landscape have been consistently reported in psychiatric and neurodevelopmental conditions, including autism. Evidence from preclinical and correlational human studies suggest that these differences arise from underlying differences in neurotransmitter systems. However, to directly assess how a given neurotransmitter system modulates functional connectivity, we need to change it and observe a shift in network connectivity. Aims & Objectives To report on how resting-state connectivity is differentially modulated by different drug classes and how responses differ between autistic and non-autistic individuals. Methods Here we establish a common framework to capture the modulation of functional connectivity within and between brain functional networks by neurosignalling systems targeted by a range of pharmacological probes. Alterations in functional connectivity are reported for seven cortical networks following activation of the serotonin, dopamine, opioid, cannabinoid and glutamate-GABA systems in neurodiverse (autistic and non-autistic) individuals. Reproducible differences in resting-state network functional connectivity, including both hyper- and hypoconnectivity of within- and between-network interactions, are reported in autism. Thus, we also assessed whether there are group-level network responsivity differences between autistic and non-autistic participants to drug challenge, or whether the response profile was primarily individual/ heterogeneous in either group. Results One common finding across pharmacological probes was that networks with reproducible baseline differences in autism (e.g. sensory and attentional networks) were also those that respond differently to drug challenge. Broadly, the cannabinoid compounds (cannabidiol and cannabidivarin) decreased functional connectivity in autistic individuals compared to non-autistic controls. By contrast, the other compounds such as the GABAergic drugs AZD7325 & arbaclofen (which activate GABAA and GABAB receptors, respectively), increased functional connectivity in autistic individuals relative to non-autistic controls. Discussion & Conclusion This is important to not only to advance our understanding of how neurotransmitter systems regulate fundamental functional networks in both the neurotypical and neurodivergent brain, but to provide a common framework for evaluating pre-existing and novel neuro-active compounds in the living human brain. We hope this work can be extended to form the basis of a human neuropharmacological reference library of neuro-active compounds across individuals and diagnoses.

Many individuals with autism spectrum disorder (ASD) experience various degrees of impairment in social interaction and communication, restricted, repetitive behaviours, interests/activities. These impairments make a significant contribution to poorer everyday adaptive functioning. Yet, there are no pharmacological therapies to effectively treat the core symptoms of ASD. Since symptoms of ASD likely emerge from a complex interplay of vulnerabilities, environmental factors and compensatory mechanisms during the early developmental period, pharmacological interventions arguably would have the greatest impact to improve long-term outcomes when implemented at a young age. It is essential therefore, that clinical development programmes of investigational drugs in ASD include the paediatric population early on in clinical trials. Such trials need to offer the prospect of direct benefit (PDB) for participants. In most cases in drug development this prospect is supported by evidence of efficacy in adults. However, the effectiveness of treatment approaches may be age-dependent, so that clinical trials in adults may not provide sufficient evidence for a PDB in children. In this white paper, we consolidate recommendations from regulatory guidelines, as well as advice from the Food and Drug Administration, USA (FDA) and the Committee for Human Medicinal Products (CHMP) consultations on various development programmes on: 1) elements to support a PDB to participants in early paediatric clinical trials in ASD, including single-gene neurodevelopment disorders, 2) aspects of study design to allow for a PDB. This white paper is intended to be complementary to existing regulatory guidelines in guiding industry and academic sponsors in their conduct of early paediatric clinical trials in ASD.

Purpose This paper aims to examine effective diagnostic and treatment pathways for attention deficit hyperactivity disorder (ADHD) in prison settings given the high prevalence of ADHD and comorbidities in the prison population. Design/methodology/approach Two studies were carried out in two separate prisons in London. Firstly, data were collected to understand the prevalence of ADHD and the comorbidities. The second study used quality improvement (QI) methodology to assess the impact of a diagnostic and treatment pathway for prisoners with ADHD. Findings Of the prisoners, 22.5% met the diagnostic criteria for ADHD. Nearly half of them were screened positive for autistic traits, with a higher prevalence of mental disorders among prisoners with ADHD compared to those without. The QI project led to a significant increase in the number of prisoners identified as requiring ADHD assessment but a modest increase in the number of prisoners diagnosed or treated for ADHD. Originality/value Despite various challenges, an ADHD diagnostic and treatment pathway was set up in a prison using adapted QI methodology. Further research is needed to explore the feasibility of routine screening for ADHD in prison and examine at a national level the effectiveness of current ADHD prison pathways.