Frontiers in Integrative Neuroscience

Autism Spectrum Disorder (ASD) encompasses a range of developmental disabilities marked by differences in social functioning, cognition, and behavior. Both genetic and environmental factors are known to contribute to ASD, yet the exact etiological factors remain unclear. Developing integrative models to explore the effects of gene expression on behavioral and cognitive traits attributed to ASD can uncover environmental and genetic interactions. A notable aspect of ASD research is the sex-wise diagnostic disparity: males are diagnosed more frequently than females, which suggests potential sex-specific biological influences. Investigating neuronal microstructure, particularly axonal conduction velocity offers insights into the neural basis of ASD. Developing robust models that evaluate the vast multidimensional datasets generated from genetic and microstructural processing poses significant challenges. Traditional feature selection techniques have limitations; thus, this research aims to integrate principal component analysis (PCA) with supervised machine learning algorithms to navigate the complex data space. By leveraging various neuroimaging techniques and transcriptomics data analysis methods, this methodology seeks to contextualize the complex genetic and phenotypic heterogeneity linked to sex differences in ASD and pave the way for tailored interventions.

The goal of this cluster analysis of comorbidities in children with Autism Spectrum Disorder (ASD) was to find potential co-occurrence between health symptoms that would not otherwise be investigated. We analyzed parent-reported data from 130,985 users of a free language-learning application. The initial cohort was stratified by ASD severity and age group to explore patterns within these subpopulations. Across these cohorts and subgroups, we observed a consistent co-occurrence of gastrointestinal symptoms, such as diarrhea and constipation, with seizures and lethargy. These results suggest that a common underlying mechanism may be driving both gastrointestinal disturbances and seizure activity in children with ASD.

In birds, like in mammals, the hippocampus critically mediates spatial navigation through the formation of a spatial map. This study investigates the impact of active exploration of a novel environment on the hippocampus of young domestic chicks, during formation of a new spatial map. Chicks that were free to actively explore the novel environment exhibited a significantly higher neural activation (measured by c-Fos expression), compared to those that passively observed the novel environment from a restricted area. The difference was limited to the anterior and the dorsolateral parts of the intermediate hippocampus. Furthermore, the nucleus taeniae of the amygdala showed a higher c-Fos expression in the active exploration group than the passive observation group. In both brain regions, brain activation correlated with the number of locations that chicks visited during the test. This suggest that the increase of c-Fos expression in the hippocampus is related to increased firing rates of spatially coding neurons. Furthermore, our study indicates a functional linkage of the hippocampus and nucleus taeniae of the amygdala in processing spatial information. Overall, with the present study, we confirm that, in birds like in mammals, exploration of novel environments activates hippocampus, which is likely related to the formation of new spatial representations. Summary statementActive exploration of a novel environment induces stronger activation of hippocampus and taeniae of domestic chicks than pure visual, passive exploration from a restricted area.

BackgroundEarly speech experiences have been proposed to contribute to the development of brain structures involved in processing spoken language. However, previous research has been limited to correlational studies. Here, we conducted an RCT with preterm neonates to determine whether increased exposure to maternal speech during NICU hospitalization is causally linked to structural white matter maturation. MethodsWe enrolled 46 preterm neonates (24-31 weeks gestational age). Participants were randomly assigned to receive increased (T: n=21) or routine (C: n=25) exposure to mothers speech. The T-group heard 10-minute audio recordings of their mothers reading a childrens story two times/hour between 10pm-6am, increasing speech exposure by 2.67 hours/day. At near-term-equivalent age, we obtained two high-angular resolution diffusion MRI (scan 1 bvalue=700, scan 2 bvalue=1500) and quantitative T1 relaxometry scans. We assessed mean diffusivity (MD), pre-registered primary outcome (NCT02847689), of the left and right arcuate fasciculus, tracts implicated in language processing. Secondary outcomes included fractional anisotropy (FA) and R1 (1/T1). FindingsT- and C-groups were equivalent on medical and demographic variables. Compared to the C- group, the T-group demonstrated significantly lower MD in the left (scan 1: mean difference{Delta} =0.11, 95% CI:0.03 - 0.19; scan 2:{Delta} =0.13, 95% CI:0.04 - 0.21) but not right arcuate (scan 1:{Delta} =0.06, 95% CI: -0.23 - 0.15; scan 2:{Delta} =0.05, 95% CI:-0.05 - 0.13). The T-group also demonstrated significantly higher FA (scan 1:{Delta} = -0.02, 95% CI:-0.04 - -0.00; scan 2:{Delta} = -0.03, 95% CI:-0.06 - -0.00) and R1 ({Delta} =-0.02, 95% CI:-0.04 - -0.01) in the left but not right arcuate. InterpretationPreterm neonates who experienced increased exposure to maternal speech during hospitalization demonstrated more mature microstructure of the left arcuate. Findings provide evidence for a causal link between speech experiences and brain development. Increasing speech exposure in the NICU may benefit preterm children. Research in Context PanelO_ST_ABSEvidence before this studyC_ST_ABSObservational studies document the importance of early speech experience for language learning and brain development in term and preterm children. Children born preterm are at-risk for adverse language outcomes that have been attributed to alterations in brain development from limited exposure to speech in the neonatal intensive care unit (NICU). However, evidence that early speech experiences causally effect the development of brain structures relevant for language is lacking. Added value of this studyThe Listening to Mom in NICU study is the first randomized controlled trial specifically designed to test the causal effects of maternal speech exposure on white matter brain development in neonates born preterm. This study demonstrates that speech experiences during neonatal development directly contribute to the maturation of the left arcuate fasciculus, a white matter tract implicated in language. Implications of all the available evidenceStudy findings advance understandings for how early speech experiences contribute to neonatal brain development. This study also demonstrates that increasing exposure to speech via audio recordings among infants born preterm could serve as an inexpensive and scalable intervention to support recovery from alterations in brain development related to the NICU experience.

ObjectiveTo determine how impairments in associative learning in autism spectrum disorder (ASD) relate to intellectual disability (ID) and early-childhood cerebellar hypoplasia. MethodsTrace and long-delay eye blink conditioning (EBC) were performed in 62 children age 11.2 years having: 1) ASD with ID (ASD+ID); 2) ASD without ID (ASD-noID); or 3) typical development (TD). The sub-second timing of conditioned eye-blink responses (CRs) acquired to a tone paired with a corneal air puff was related to brain structure at age 2 years and clinical measures across ages 2-12 years. Because CR timing is influenced strongly by cerebellar function, EBC was used to test hypotheses relating cerebellar hypoplasia to ASD. ResultsChildren with ASD+ID showed early-onset CRs during trace EBC that were related to early-childhood hypoplasia of the cerebellum but not of the cerebral cortex, hippocampus, or amygdala. Children with ASD-noID showed early-onset CRs only during long-delay EBC without cerebellar hypoplasia. Using EBC measures, logistic regression detected ASD with 81% sensitivity and 79% specificity while linear discriminant analysis separated ASD subgroups based on ID but not ASD severity. MRI of additional 2-year-olds with ASD indicated that early-onset CRs during trace EBC revealed ASD+ID more readily than cerebellar hypoplasia, per se. ConclusionsEarly-childhood cerebellar hypoplasia occurs in children with ASD+ID that demonstrate early-onset CRs during trace EBC. Trace EBC reveals the relationship between cerebellar hypoplasia and ASD+ID likely by engaging cerebro-cerebellar circuits involved in intellect. We emphasize that the cerebellum optimizes sensory-motor processing at sub-second intervals, impairments of which may contribute to ID.

BackgroundAltered patterns of eye-movements during scene exploration, and atypical gaze preferences in social settings, have long been noted as features of the Autism phenotype. While these are typically attributed to differences in social engagement and interests (e.g., preferences for inanimate objects over face stimuli), there are also reports of differential saccade measures to non-social stimuli, raising the possibility that fundamental differences in visuo-sensorimotor processing may be at play. Here, we tested the plasticity of the eye-movement system using a classic saccade-adaptation paradigm to assess whether individuals with ASD make typical adjustments to their eye-movements in response to experimentally introduced errors. Saccade adaptation can be measured in infants as young as 10 months, raising the possibility that such measures could be useful as early neuromarkers of ASD risk. MethodsSaccade amplitudes were measured while children and adults with ASD (N=41) and age-matched typically developing (TD) individuals (N=68) made rapid eye-movements to peripherally presented targets. During adaptation trials, the target was relocated from 20-degrees to 15-degrees from fixation once a saccade to the original target location was initiated, a manipulation that leads to systematic reduction in saccade amplitudes in typical observers. ResultsNeither children nor adults with ASD showed any differences relative to TD peers in their abilities to appropriately adapt saccades in the face of persistently introduced errors. ConclusionsOf the three studies to date of saccade adaptation in ASD, none have shown frank deficits in saccade adaptation. Unlike prior studies, we found no evidence for a slower adaptation rate during the early adaptation phase, and no of evidence greater variance of saccade amplitudes in ASD. In post-hoc analysis, there was evidence for larger primary saccades to non-adapted targets, a finding requiring replication in future work.

Several disciplines have approached the relationship between autism spectrum disorder (ASD) and music, but most of this understanding comes from cognitive sciences. This complex relationship has been studied by exploring how music-based interventions (MI) can benefit individuals with ASD. This systematic review and meta-analysis synthesize a range of evidence regarding the therapeutic effects of music on different aspects, including communication, behavior, social engagement, attention, and quality of life for those with ASD. Additionally, it contextualizes these effects within current research on the musical perception and processing abilities of ASD individuals, emphasizing how they perceive and process music. The studies reviewed employ a variety of methodologies, from randomized controlled trials to qualitative research, showcasing a wide array of interventions such as active music-making, music listening, and improvisational techniques. Despite substantial heterogeneity across studies, the findings point to a moderate overall benefit of MI, particularly in areas such as social interaction, expressive language, and quality of life. Given the evidence supporting the context-sensitive and domain-specific benefits of musical abilities in individuals with ASD, along with the positive outcomes highlighted in various studies, we conclude that music represents a valuable therapeutic tool for ASD. It engages individuals on emotional, cognitive, and social levels, providing a non-invasive and enjoyable way to enhance therapeutic outcomes. Future research should focus on individual differences, harmonization of outcome measures, and long-term effectiveness, paving the way for more personalized and neurodiversity-affirming intervention models.

BACKGROUNDIn late 2016, US diplomats stationed in Havana began presenting with a variety of neurological manifestations that proved difficult to diagnose. Though previous studies suggested a likely association with brain injury, the mechanism of injury, brain regions involved, and etiology remained unknown. METHODSWe conducted a multimodal study examining 26 Canadian diplomats and their family members, the majority of whom presented with symptoms similar to their American counterparts while residing in Havana. Assessments included a medical history, self-reported symptom questionnaires, cognitive assessments, blood tests, and brain imaging assessments (magnetic resonance imaging (MRI) and magnetoencephalography (MEG)). Individuals showing signs of brain injury underwent further neurological, visual, and audio-vestibular assessments. Eight participants were tested both before and after living in Havana. RESULTSOur assessment documents multiple functional and structural impairments, including significant spatial memory impairment, abnormal brain-stem evoked potentials, degradation of fibre tracts in the fornix and posterior corpus callosum, blood-brain barrier injury to the right basal forebrain and anterior insula, and abnormal paroxysmal slowing events of cortical activity. Subsequent mass-spectrometry and blood analyses documented reduced serum cholinesterase activity and the presence of organophosphates (Temephos) and pyrethroid metabolites (3-phenoxybenzoic acid or 3-BPA). CONCLUSIONSOur findings confirm brain injury, specify the regions involved, and raise the hypothesis of overexposure to cholinesterase inhibitors as a plausible etiology. If correct, our hypothesis bears public health ramifications (see Discussion) and suggests a course of action for reducing exposure in the future. FUNDINGGlobal Affairs Canada.

IntroductionThree-spined stickleback fish are famous for their diversity and charismatic social behavior. However, there are few neuroanatomical resources for studying the neural and brain mechanisms underlying their fascinating behavior. Methods and ResultsWe identify 11 brain areas important for social behavior by referencing brain atlases for six other teleost fishes. Brain regions were identified via neuroanatomical landmarks and we characterized the presence / absence of tyrosine hydroxylase (TH), a key gene product of the dopaminergic system, in those regions. Comparing the neuroanatomical location of these regions in the stickleback brain and the expression of TH therein to that of other fish species highlights similarities and differences and the need for a brain atlas specific to sticklebacks. This resource serves as a map of the location of regions important for social behavior in the stickleback brain. ConclusionThis resource will help guide future studies connecting gene function to social behavior through the brain and will enable future work to understand the evolution of neural mechanisms that contribute to the diversity of social behavior in this emerging model organism.

Background and ObjectivesApproximately 25% of pediatric patients who undergo cerebellar tumor resection develop cerebellar mutism syndrome (CMS). Our group recently showed that damage to the cerebellar outflow pathway is associated with increased risk of CMS. Here, we tested whether these findings replicate in an independent cohort. MethodsWe evaluated the relationship between lesion location and the development of CMS in an observational study of 56 pediatric patients who underwent cerebellar tumor resection. We hypothesized that individuals that developed CMS after surgery (CMS+), relative to those that did not (CMS-) would have lesions that preferentially intersected with: 1) the cerebellar outflow pathway, and 2) a previously generated lesion-symptom map of CMS. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods (https://osf.io/r8yjv/). ResultsWe found supporting evidence for both hypotheses. Compared with CMS-patients, CMS+ patients (n=10) had lesions with greater overlap with the cerebellar outflow pathway (Cohens d=.73, p=.05), and the CMS lesion-symptom map (Cohens d=1.1, p=.004). DiscussionThese results strengthen the association of lesion location with risk of developing CMS and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to pediatric cerebellar tumors.

Differences in looking to and processing of audiovisual speech have been theorized to contribute to heterogeneity in language ability in autistic children. Differential audiovisual speech processing has been indexed by event-related potentials (ERPs), specifically via amplitude suppression in response to audiovisual versus auditory-only speech, and linked with vocabulary in school-aged children. This study used an intact-group comparison and concurrent correlational design in infant siblings of autistic children (Sibs-Autism) and non-autistic children (Sibs-NA) to determine whether amplitude suppression is (a) present in infancy, (b) different in Sibs-Autism versus Sibs-NA, and (c) related to looking to audiovisual speech and language abilities. We collected EEG data from 54 infants aged 12-18 months (29 Sibs-Autism; 25 Sibs-NA) while they viewed videos of audiovisual and auditory-only speech, as well as eye tracking and language data. We found significant amplitude differences at the N2 ERP component in response to audiovisual versus auditory-only speech but no significant group differences in ERP amplitudes. Associations between looking to audiovisual speech, amplitude effects, and language were moderated by group, chronological age, and biological sex. Our findings suggest that differential audiovisual speech processing is present in 12-18-month-olds and may explain heterogeneity in looking to audiovisual speech and emerging language ability.

This study aimed to determine discrepancies in the urinary glycosaminoglycan profiles of autism spectrum disorder (ASD) patients (n=9) when compared with those from healthy volunteers (HVs, n=3). The guardians and/or educators for each participant also returned a validated Autism Behavior Checklist (ABC). The urinary chondroitin sulfate (CS) concentration was 46.1% lower in the ASD group than in the HV group. The ABC score and the urinary CS concentration were negatively correlated (Spearmans {rho}=- 0.2635), indicating that as the severity of the clinical aspect of this disorder increased, the urinary CS concentration decreased. These results suggest that low CS concentrations in the urine may be associated with ASD, and could be measured using a fast and low-cost method for diagnostics.

ObjectiveThis study examined whether baseline reports of adverse childhood experiences (ACEs) and early life adversity (ELA) were associated with subsequent head/neck injury or probable brain injury in the Adolescent Brain Cognitive Development (ABCD) Study(R) cohort. SettingABCD Study(R) cohort ParticipantsABCD Study(R) data release 5.0 provided baseline and partial longitudinal data through Year 4. Inclusion required at least one follow-up timepoint, data to compute the ACEs or ELA score, sex, and attention-deficit/hyperactivity disorder (ADHD) diagnosis status. The final sample included 10,853 participants for ACEs analyses and 10,850 ELA analyses. DesignProspective observational design. Main MeasuresHead and/or neck injuries and probable brain injuries were assessed using the caregiver-reported Ohio State University Traumatic Brain Injury Identification Method Short Form. We used previously published recommendations for the ABCD study to calculate a proxy ACEs score and a broader measure of ELA using both caregiver and youth report at baseline. Age, gender, race/ethnicity, primary caregiver education, childs history of ADHD, report of head/neck or probable brain injury at baseline, and broken bone injury at baseline or follow-up were covariates in logistic regression models examining the association between risk of head/neck injury or probable brain injury with ACEs or ELA. ResultsExposure to more adversity (ACES: Odds Ratio [95% Confidence Interval] OR[95%CI]=0.04[0.001,0.08]; ELA: OR[95%CI]=0.05[0.01,0.08]) was associated with higher odds of sustaining a head or neck injury at any of the follow-up time points but not of probable brain injury (ACES: OR[95%CI]=0.002[-0.08,0.08]; ELA: OR[95%CI]=0.01[-0.06,0.07]). ConclusionLimited public knowledge of and reliance on caregiver report of head/neck injury increases misclassification bias and underscores the need for improved education and measurement strategies. We observed a stronger association between ELA and head/neck injury, potentially reflecting differences in disclosure and awareness rather than due to types of exposure.

BackgroundAutism spectrum disorder (ASD) is defined behaviorally, but measures that probe underlying neural mechanisms may provide clues to biomarker discovery and brain-based patient stratification with clinical utility. Phase-amplitude coupling (PAC) has been posited as a measure of the balance between top-down and bottom-up processing in cortex, as well as a marker for sensory processing and predictive coding difficulties in ASD. We evaluate differences in PAC metrics of resting-state brain dynamics between children with and without ASD and relate PAC measures to age and behavioral assessments. MethodsWe analyzed electroencephalography data collected by the Autism Biomarkers Consortium for Clinical Trials, including 225 (192 male) ASD and 116 (81 male) typically-developing children aged 6-11 years. We evaluated the strength and phase preference of PAC and the test-retest reliability of PAC across sessions. ResultsThere was significantly increased alpha-gamma and theta-gamma PAC strength in ASD. When considering all participants together, we found significant associations of whole brain theta-gamma PAC strength with measures of social communication (Beta = 0.185; p = 0.006) and repetitive behaviors (Beta = 0.166; p = 0.009) as well as age (Beta = 0.233; p < 0.0001); however, these associations did not persist when considering the ASD group alone. There are also group differences in theta-gamma phase preference. ConclusionsThis large, rigorously collected sample indicated altered PAC strength and phase bias in ASD. These findings suggest opportunities for back-translation into animal models as well as clinical potential for stratification of brain-based subgroups in ASD.

BackgroundFragile X Syndrome (FXS) is a rare, neurodevelopmental disorder caused by a mutation to the Fragile X messenger ribonucleoprotein 1 (Fmr1) gene and characterized by sensory processing abnormalities and sensitivities, including neural auditory oscillatory disruptions and reduced neural entrainment to chirp stimuli. The present study aims to evaluate the 40 Hz auditory steady state response (ASSR) in FXS to evaluate stimulus representation maintenance in FXS. MethodsAdolescents and adults (N = 67; 34 FXS and 33 age, sex-matched typically developed controls (TDC)) completed a 40 Hz auditory steady state task during electroencephalography (EEG). Time-frequency analyses using Morlet wavelets were completed to evaluate intertrial phase coherence (ITC) and event-related spectral perturbation (ERSP), including characterization of the transient and sustained components of the 40 Hz ASSR. ResultsBoth ITC (p = .003) and ERSP (p = .004) at 40 Hz were reduced for FXS compared to TDC. Interestingly, TDC exhibited a significantly elevated early, transient component (100 - 400 ms) which reduced in both ITC and ERSP during transition to the sustained component (650 - 3000 ms) whereas FXS were consistently reduced across the ASSR suggesting a reduced ability for FXS to mount a transient response. ConclusionsIndividuals with FXS exhibit robust reductions in magnitude and temporal precision of neural entrainment to the steady state stimulus. The reduced ability to mount a transient response may represent reduced GABAergic modulation where the overall reduction in ITC and ERSP may reflect reduced excitatory/inhibitory balance between NMDA and GABAergic input.

Background and ObjectivesPreterm birth is associated with altered white matter development and long-term neurodevelopmental impairments. Skin-to-skin care (kangaroo care) has well-documented benefits for physiological stability and bonding, but its association with neonatal brain structure remains unclear. This study explored the association between in-hospital skin-to-skin care and neonatal white matter microstructure in frontal and limbic pathways that are linked to stress regulation and socio-emotional development, processes potentially influenced by affective touch during skin-to-skin care. MethodsThis retrospective study analyzed electronic medical records and diffusion MRI data collected from 86 preterm infants (<32 weeks gestational age) in a single NICU. Skin-to-skin care exposure was quantified as total duration (minutes/instance) and rate (minutes/day) of sessions. Diffusion MRI scans obtained before hospital discharge assessed mean diffusivity (MD) and fractional anisotropy (FA) in the cingulate, anterior thalamic radiations (ATR), and uncinate fasciculus. Hierarchical regression models examined associations between skin-to-skin care and white matter microstructure, adjusting for gestational age, health acuity, postmenstrual age at scan, and MRI coil type. Sensitivity analyses controlled for socioeconomic status and NICU visitation frequency. ResultsSkin-to-skin care duration was positively associated with MD in the cingulate (B = 0.002, p = 0.016) and ATR (B = 0.002, p = 0.020). Skin-to-skin care rate was also positively linked to MD in the ATR (B = 0.040, p = 0.041). Skin-to-skin care duration and rate were not associated with FA in the cingulate but skin-to-skin duration and rate were negatively associated with FA in the ATR (duration: B =-0.001, p = 0.020; rate: B =-0.017, p = 0.008). No significant associations were found for the uncinate fasciculus. Findings remained robust after adjusting for socioeconomic status and visitation frequency. DiscussionThis study provides novel evidence linking in-hospital experiences of skin-to-skin care to neonatal white matter development. These findings have important implications for understanding how family-centered neuroprotective practices, such as skin-to-skin care, may affect brain development to improve long-term developmental outcomes.

BackgroundApproximately 1 in 4 children who sustain an acquired brain injury (ABI) have attention difficulties impacting education, employment, and community participation. These difficulties arise from dysfunction in attention-related brain networks, incentivising the use of transcranial direct current stimulation (tDCS). Objective/HypothesisWe investigated whether a single tDCS session improved attention following childhood ABI and whether baseline structural connectivity (sc), functional connectivity (fc), attention, and/or simulated electric fields (E-field) explained variability in response. MethodsIn a randomised, single-blind, within-subject, sham-controlled trial, 15 children with ABI (mean 12.7 years) and 15 healthy controls (HCs) received three single tDCS sessions (1mA dorsolateral prefrontal cortex [dlPFC], 1mA inferior frontal gyrus [IFG], sham; 20min) during gamified attention training. We examined post-intervention changes in attention according to flanker and stop signal reaction time (RT). We used multi-modal analyses (high-density electroencephalography [HD-EEG], diffusion tensor imaging, magnetic resonance imaging) to investigate inter-individual variability in tDCS response, according to associations between RT change and baseline fc, sc, attention, and E-fields. ResultsAlthough no effect of active versus sham tDCS was found overall, participants with lower theta or higher gamma default mode network connectivity and poorer attention at baseline showed greater response to tDCS. Higher E-fields were associated with greater response. No serious adverse effects occurred. ConclusionsA single tDCS session targeting dlPFC or IFG did not improve attention following pediatric ABI. We demonstrated how HD-EEG source-based connectivity may be used to personalise tDCS. Future research should explore whether personalization, and/or repeated tDCS sessions can improve attention following pediatric ABI.

Abstract Background: Australian age standardized MND mortality increased steadily from 1959 and peaked around 2010 to 2012 and then declined steadily to 2022. The environmental drivers of this trend remain poorly understood. Historical exposure to leaded petrol, reflected in long term population blood lead levels, has been proposed as a potential contributor to contemporary MND risk due to the neurotoxicity and long latency associated with lead exposure. Methods: We examined national MND mortality in Australia from 1996 to 2022 in relation to reconstructed cumulative population blood lead levels derived from digitised Kristensen (2015) data, forward shifted by 20 years to account for exposure disease latency. Annual insecticide use per capita was included as a secondary exposure, and calendar year was used to adjust for secular trends. A generalized additive model (GAM) was fitted using a 4-degree-of-freedom spline for cumulative blood lead levels and linear terms for insecticides and year. Model fit was evaluated using coefficient estimates, joint significance testing for the spline term, and visual inspection of partial dependence smooths. Results: The GAM model explained approximately 58.9% (adjusted R2 = 49.1%) of year to year variation in Australian age-standardised MND mortality rates. The spline for cumulative blood lead levels was highly significant (p = 0.00024), indicating a strong non linear association between long term lead exposure and MND mortality. In contrast, insecticide use showed no statistically meaningful independent effect after adjustment (p = 0.39). Year demonstrated a borderline significant positive association (p = 0.072). Partial dependence plots revealed substantial curvature in the lead MND exposure response relationship, with different historical lead burdens corresponding to distinct changes in predicted MND mortality. Conclusions: These findings support a robust, non linear association between historical population lead exposure and contemporary MND mortality in Australia, independent of secular trends and insecticide use. The results strengthen the hypothesis that past leaded petrol emissions may contribute to current MND risk, consistent with the long biological persistence and delayed neurotoxic effects of lead. Further work integrating individual level data, biomarker validation, and mechanistic studies is warranted to clarify causality and quantify population attributable risk.

Neurobiological research focuses on a small number of model organisms, broadening the pool of animals used in research may lead to important insights into the evolution of nervous systems. The ctenophore is emerging as a promising model, but we are currently lacking an understanding into the relationship between behaviour and environment which is in part due to a lack of a standardised long-term laboratory husbandry system. We established a collection and husbandry system for wild caught Pleurobrachia pileus. We examined the behavioural profile of the animals over time in this controlled environment. We could reliably catch them on a seasonal basis, and we could keep the animals alive in our specialised aquarium system for months at a time. P. pileus spends most of the time in an inactive drifting state which is interspersed with periods of one of 5 active behaviours. The most common active behaviours are tentacle resetting and feeding. The longest duration behaviours include swimming up or down. Time of day does not appear to alter their behavioural profile. Gaining a better understanding of the behaviour of these animals has important implications for systems and evolutionary neuroscience.

BackgroundDifferences in sensory processing are a core feature of autism spectrum disorder. Hyper- and hyporesponsivity to sensory stimuli have historically been conceptualized as separate constructs but may co-occur within individuals. Sensory processing may impact both lower and higher-level cognitive processes; thus, it is crucial to understand the relationships between hyper- and hyporesponsivity within and across modalities, as well as the relationship between sensory processing and other aspects of development in both autistic and typically developing (TD) children. MethodsIn 3-4-year-old children (n=41 autism; n=37 TD), we assessed relationships between sensory hyper- and hyporesponsivity both within and across visual, auditory, touch, and oral sensory modalities as measured by caregiver report. Secondary analyses evaluated relationships between sensory responsivity, social communication, and cognitive abilities. FindingsWe found a positive correlation between sensory hyper- and hyporesponsivity ({rho} = .788, p < .001). These associations persisted within groups and within and across modalities. There are positive associations between sensory responsivity and social interaction, communication, and nonverbal developmental quotient, with associations between sensory responsivity and social communication driven by associations within the autism group. InterpretationThe positive correlations between hyper- and hyporesponsivity both within and across sensory modalities, which we term the "Sensory Paradox," may provide key clues to understanding sensory processing in autism and other neurodevelopmental disorders by pointing towards neural circuit-level mechanisms that may underlie neurodevelopmental conditions. FundingThis study was funded by NIH/NINDS 1R01NS134948-01 (ARL), NIMH T32MH112510 (KDC), the Simons Foundation Autism Research Initiative (Award number 648277, ARL), and the Eagles Autism Foundation (ARL). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSUp to 95% of autistic individuals are impacted by sensory processing differences. Across the full range of the autism spectrum, including individuals with profound ASD and self-advocates who speak publicly on issues of neurodiversity, improving sensory processing challenges is repeatedly noted as a common goal that would improve quality of life. Classical medical evaluation of sensory processing typically focuses on whether the structural pathways for transmission of sensory information are intact. The modulation of sensory information as it traverses these pathways, however, is a field ripe for further understanding. Initial reports have identified both hyper- and hyporesponsivity to sensory stimuli in autism, with some overlap between the two patterns of behavior. Added value of this studyThis study demonstrates the seemingly paradoxical finding that hyper- and hyporesponsivity are strongly positively correlated in both autistic and typically developing toddlers. This positive correlation persists within groups and within individual sensory modalities (sight, sound, touch, and oral), as well as across modalities. Implications of all of the available evidenceThe current findings, taken together with prior literature, support the Sensory Paradox - a framework for understanding sensory processing and the resulting sensory experience of autistic individuals which may also have key implications for a wider variety of neurological, psychiatric, and developmental conditions. Rather than considering hyper- and hyporesponsivity as static and opposing constructs, future work on the neurobiology, diagnosis, and management of sensory processing will benefit from considering the variable and context-dependent nature of sensory processing within individuals.