Biology subjects

Foxe, J. J.

Publications and source records attributed to Foxe, J. J..

At least 19 recordsLinked to original sources

bioRxiv2026

Neural and Gait Adaptations to Dual-Task Demands in Children and Young Adults: A Mobile Brain-Body Imaging (MoBI) Study.

Cognitive-motor interactions describe the complex interplay underlying how the brain manages concurrent demands on motor and cognitive processing. Yet, how cognitive-motor interactions present across childhood and young adulthood remains understudied, particularly through multi-modal methods which include neurophysiology. We investigated development of cognitive-motor interactions using a dual-task study design including simultaneous motor (walking) and cognitive (visual Go-NoGo) tasks. Using mobile brain-body imaging, (MoBI), we recorded simultaneous EEG, gait kinematics, and task performance. 61 neurotypical 8-to-30-year-olds completed the Go-NoGo while seated or walking on a treadmill. With increased age, participants became faster and more accurate on the task, walking became less variable, and N200 and P300 ERP amplitudes increased. Two distinct effects of cognitive-motor interactions emerged with age. An N200 amplitude attenuation when walking became exaggerated with age, suggesting older participants engaged greater neurophysiological flexibility to support their improved task performances, whereas children performed less well and may not have needed to recruit the same adaptive neural mechanisms. Additionally, an attenuation of stride variability during dual-task walking lessened with age, demonstrating robust motor development under dual-task conditions. These findings demonstrate a distinct pattern of changes to cognitive-motor interactions through development. Future research can examine how this pattern varies in different developmental conditions.

neuroscience↗

bioRxiv2026

Functional ultrasound imaging reveals pathway-specific visual system reorganization in young Cln3-/- mice

CLN3 disease, or juvenile Batten disease, is a neurodegenerative lysosomal storage disorder in which visual impairment is typically the earliest clinical manifestation. Although retinal pathology has been extensively studied, functional alterations within central visual pathways remain poorly understood. Here, we used functional ultrasound (fUS) imaging to characterize visually evoked activity across central visual circuits in young Cln3 knockout (Cln3-/-) mice before the onset of severe retinal degeneration. Visually evoked hemodynamic responses were quantified in regions spanning the geniculostriate and extrageniculate visual pathways, including cortical, thalamic, and midbrain regions. To assess regional pathological burden, accumulation of subunit c of mitochondrial ATP synthase (SCMAS), a pathological marker of CLN3 disease, was examined using immunohistochemistry. We found that Cln3-/- mice exhibited pathway-specific alterations in visually evoked activity. Regions along the extrageniculate pathway, including the midbrain, posterior thalamus, and anterior secondary visual cortex, showed enhanced activation relative to wild-type controls. In contrast, activation within the geniculostriate pathway was reduced in the anterior thalamus and remained unchanged in the primary and posterior secondary visual cortex. SCMAS accumulation was elevated across all examined visual regions in Cln3-/- mice relative to wild-type controls, with greater accumulation observed in geniculostriate regions than in extrageniculate regions. These findings demonstrate early pathway-specific functional and pathological alterations in the visual system of Cln3-/- mice, suggesting pathway-level reorganization of central visual processing. This study advances understanding of central visual dysfunction in CLN3 disease and highlights fUS imaging as a sensitive approach for detecting early functional abnormalities in neurodegenerative disorders.

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bioRxiv2026

Asymmetric neural dynamics of visuospatial attention in autism spectrum disorder

BackgroundSelective attention enables the prioritization of behaviorally relevant information in complex sensory environments. Despite substantial evidence for altered attention in autism spectrum disorder (ASD), the neurophysiological mechanisms underlying these differences remain poorly understood. MethodsHere, we integrate high-density electroencephalography (EEG), pupillometry, and behavioral measures collected during a cued covert visuospatial selective attention task to characterize mechanisms of spatial attention in children and adolescents with ASD (n = 18; 13.4 {+/-} 3.0 YO), and how they differ from age- and IQ- matched individuals with typical-development (TD) (n = 21; 14.7 {+/-} 3.8 YO). ResultsBoth groups demonstrated high target detection accuracy and comparable response times, with no significant between-group differences in behavioral performance. Furthermore, neurophysiological measures demonstrated that during leftward attention, both TD and ASD participants exhibited canonical attentional processes, including lateralized anticipatory parieto-occipital alpha modulation and enhanced P1 sensory responses to attended stimuli. Additionally, across both groups, trial-level analyses revealed that decreased anticipatory alpha power and increased P1 amplitude contralateral to the attended hemifield were associated with faster reaction times. In contrast, there were notable group differences in the neural dynamics supporting rightward spatial attention. TD participants showed early sensory gain (P1 modulation) without alpha-band modulation, whereas ASD participants exhibited modulation of posterior alpha power without effective sensory gain. Interestingly, for rightward attention, only P1 amplitude predicted reaction time, and this was the case for both groups. Resting-state alpha dynamics did not differ between groups, indicating that the attended hemifield differences reflect task-dependent differences in attentional control rather than baseline oscillatory differences. LimitationsLimitations include modest sample size and restriction to autistic individuals with relatively low support needs, which may limit the generalizability of these findings to the broader autism spectrum. ConclusionsThe similarity of leftward attention mechanisms across groups, which includes intact recruitment of anticipatory alpha modulation, argues against a global disruption of basic visuo-spatial attentional function in autistic individuals with low support needs. However, group differences emerged specifically during rightward attention, where ASD participants showed a more uniform pattern of oscillatory modulation, warranting further investigation. Collectively, these findings provide novel insight into the neural architecture of visuospatial attention in ASD, revealing how preparatory oscillatory activity shapes early sensory responses and behavior during selective attention.

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bioRxiv2026

Distinct Auditory Thalamocortical Pathologies Underlie Emerging Neurophysiological Dysfunction in a Cln3 Mouse Model of Batten Disease

CLN3 disease, the most common form of the Neuronal Ceroid Lipofuscinoses (NCLs), causes progressive cognitive decline and language impairment in humans. A pathological hallmark is the accumulation of storage material within neuronal lysosomes resulting from mutations in the CLN3 gene. We previously identified parallel deficits in auditory duration mismatch negativity (MMN), an electroencephalography (EEG)-based marker of auditory change detection, in individuals with CLN3 disease and in Cln3-/- mice. MMN-dependent auditory change detection relies on sensory-memory comparison mechanisms. However, the anatomical and neurophysiological substrates underlying this response in CLN3 disease remain unclear. Here, we investigated central auditory dysfunction in Cln3-/- mice by integrating immunohistochemical mapping of lysosomal storage pathology, using the canonical marker Subunit C of Mitochondrial ATP Synthase (SCMAS), with EEG analysis of auditory evoked potentials (AEPs). Neuropathological analyses revealed age-dependent and sex-divergent SCMAS accumulation across the auditory thalamocortical circuit, including the excitatory auditory thalamus, the inhibitory thalamic reticular nucleus, and the primary auditory cortex. In parallel, Cln3-/- mice exhibited age- and sex-dependent alterations in AEPs relative to wild-type controls. Importantly, an integrated measure of auditory thalamocortical SCMAS accumulation accounted for a substantial portion of age- and sex-matched variation in AEP responses, with stronger associations for the early N1 component than the later MMN component. Together, these findings link age-dependent and sex-divergent auditory neurophysiological deficits to region-specific lysosomal storage pathology within the auditory thalamocortical circuit in the Cln3-/- mouse model. This integrated functional-anatomical framework provides insight into circuit vulnerability and supports the development of translational neurophysiological biomarkers for CLN3 disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/729359v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8dc148org.highwire.dtl.DTLVardef@8c918borg.highwire.dtl.DTLVardef@a7483dorg.highwire.dtl.DTLVardef@77d171_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISCMAS accumulates across the auditory thalamocortical circuit in Cln3-/- mice C_LIO_LIAccumulation shows distinct age- and sex-dependent regional trajectories C_LIO_LICln3-/- mice exhibit progressive alterations in auditory evoked potentials C_LIO_LIThalamic pathology is strongly associated with the early auditory N1 response C_LIO_LIHistology-EEG integration links circuit pathology to auditory dysfunction C_LI

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bioRxiv2026

Instability of Alpha Oscillatory States in Autism and Familial Liability: Evidence from Burst-Resolved High-Density Electroencephalography (EEG)

Atypical sensory experiences are highly prevalent in autistic children and include both hyper- and hypo-responsivity, often accompanied by sensory overload. Alpha oscillations (7-13 Hz), which dynamically regulate cortical excitability, represent a plausible neural mechanism underlying these phenomena: reduced alpha activity is associated with enhanced sensory responsiveness, whereas increased alpha supports suppression of external input. Although decreased alpha power has been repeatedly reported in autism, it remains unclear whether this reduction reflects lower oscillatory amplitude or reduced temporal stability of alpha rhythms, two mechanisms with distinct neurophysiological implications. To better characterize alpha activity in autism, we examined resting-state alpha dynamics in non-autistic children (NA; n = 39), autistic children (AU; n = 52), and siblings of autistic children (SIB; n = 26), aged 8-14 years. We combined traditional broadband measures of relative alpha power, parametric separation of periodic and aperiodic activity, and single-event analyses that quantify the temporal structure of alpha oscillations. Both broadband relative alpha power and periodic alpha power were reduced in autism over parietal regions, replicating prior findings. Importantly, ordinal analyses revealed an intermediate profile in siblings, supporting a liability-related gradient of alpha alterations. However, single-event analyses demonstrated that the average amplitude of individual alpha bursts did not differ between groups. Instead, autistic children showed significantly shorter alpha burst duration and reduced alpha abundance (i.e., proportion of time occupied by rhythmic alpha episodes), with siblings again exhibiting intermediate values. Linear regression analyses confirmed that reductions in relative and periodic alpha power were primarily driven by decreased alpha abundance rather than diminished burst amplitude. These findings indicate that altered alpha activity in autism reflects reduced temporal stability and density of alpha events rather than weaker oscillatory amplitude per se. Reduced persistence of alpha rhythms may therefore represent a neural marker of altered cortical excitability and sensory regulation in autism. Lay summaryAutistic children often experience the world differently at the sensory level, including being more easily overwhelmed by sounds, lights, or other stimuli. In this study, we looked at a type of brain activity called alpha rhythms, which help regulate how strongly the brain responds to incoming information. We found that, in autistic children, these alpha rhythms were not weaker when they occurred, but they lasted for a shorter time and happened less often. Siblings of autistic children showed an intermediate pattern. These results suggest that sensory differences in autism may be linked to less stable brain rhythms that normally help control sensory input. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/716324v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1be733dorg.highwire.dtl.DTLVardef@7fea49org.highwire.dtl.DTLVardef@1ee9124org.highwire.dtl.DTLVardef@17af139_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2026

Frontal theta phase modulates asymmetric posterior neural mechanisms of spatial attention

Selective attention enables prioritization of behaviorally relevant information through coordinated control of neural excitability. Although theta-band (3-7 Hz) rhythms are implicated in top-down attentional sampling in non-human primates, how intrinsic theta phase organizes sensory gain and behavior in humans, and whether this control operates symmetrically across hemispheres, remains unknown. We recorded electroencephalography (EEG) and pupillometry in typically developing human participants (n = 21; 14.7 {+/-} 3.8 YO) performing a covert spatial attention task. Behaviorally, participants responded faster during leftward relative to rightward attention. This behavioral asymmetry was paralleled in the neural data: anticipatory modulation of parieto-occipital alpha and beta power emerged selectively during leftward attention, whereas rightward attention did not recruit comparable posterior oscillatory processes. Mechanistically, ipsilateral fronto-central theta phase emerged as a potential driver of this asymmetry. Intrinsic theta phase predicted trial-by-trial reaction time (RT) in a cue-direction-specific manner. During leftward attention, 3-Hz theta-phase over left fronto-central cortex modulated behavior and was significantly coupled to coordinated posterior alpha-band activity. In contrast, 6-7-Hz theta-phase over right fronto-central cortex modulated behavior during rightward attention but showed no relationship with alpha or beta modulation; instead, it modulated early sensory gain, indexed by P1 amplitude. Consistent with these distinct architectures, RT was jointly predicted by lower pre-stimulus alpha power and higher P1 amplitude over the attended hemisphere during leftward attention, whereas only P1 amplitude predicted performance during rightward attention. Resting-state alpha power did not differ across hemispheres, indicating that these effects were task-evoked rather than baseline spectral differences. Critically, older participants, who demonstrated enhanced behavioral performance, also exhibited a larger hemispheric asymmetry. Together, these findings reveal developmentally emerging, direction-specific neural control dynamics underlying human spatial attention. Significance StatementSpatial attention is often assumed to rely on symmetric neural mechanisms across left and right space. Using EEG in typically developing children and adolescents, we show that intrinsic theta rhythms organize attention through direction-specific control architectures. Leftward attention engages slower frontal theta (3-Hz) that coordinates posterior alpha and beta activity, consistent with oscillatory sensory gating. Rightward attention instead relies on faster theta (6-7-Hz) that modulates early sensory responses without coordinated alpha dynamics. These asymmetric mechanisms occur despite lack of hemispheric differences in resting alpha activity, indicating that they emerge during active control rather than reflecting baseline biases. These findings reveal that human attentional sampling is rhythmically organized but fundamentally asymmetric across space.

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bioRxiv2026

Atypical somatosensory adaptation in adults on the autism spectrum: a high-density electrophysiological (EEG) mapping study.

Adaptation to repetitive sensory inputs promotes efficient neural processing by attenuating responses to redundant information and reallocating resources to novel stimuli. Reduced adaptation has been proposed to contribute to atypical sensory reactivity in autism, but the physiological mechanisms underlying tactile adaptation remain poorly understood. Here, we examined short-term adaptation to repetitive vibrotactile stimulation in autistic and neurotypical adults using high-density electrophysiological recordings. Fifty participants (18-44 years; 25 autistic; 25 neurotypical), received sequences of four brief vibrations to the index fingertip while viewing silent videos. Neural responses were analyzed for an early negative deflection (N1, [~]100 milliseconds) indexing basic stimulus recognition, and a later positive deflection (P2, [~]200-300 milliseconds) indexing higher-order contextual and attentional processing. Adaptation was quantified as changes in response magnitude across the four vibrations. The N1 did not differ between groups, showing minimal change across repetitions, indicating comparable processing of basic tactile features. In contrast, the P2 was significantly larger overall in the autistic group. Across both groups, responses to the first vibration in each sequence were greater than responses to subsequent vibrations, reflecting re-sensitization following the inter-sequence interval. Autistic participants exhibited consistently amplified P2 responses to initial vibrations, suggesting heightened re-sensitization rather than impaired within-sequence adaptation. Associations between neural responses and clinical measures of autistic traits and tactile sensitivity were modest. These findings indicate that autistic adults show amplified higher-order neural responses to tactile input alongside preserved short-term adaptation. Heightened re-sensitization to repeated touch may reflect shortened refractory periods, contributing to sensory hyper-reactivity and increased perceptual load.

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bioRxiv2026

Neural markers of visual working memory during an upper extremity movement-coupled task: a mobile brain-body imaging (MOBI) study.

Optimal goal-directed behavior in everyday life involves the appropriate coupling of cognition and movement. In this study we employed a mobile brain-body imaging (MoBI) system that integrated time-synchronized high-density electroencephalography with 3-dimensional motion capture during a touchscreen visual working memory task requiring dynamic upper extremity reach responses. Using this framework we examined how increasing memory load (i.e. from 1-disc to 4-discs) influences behavior and scalp-recorded neural activity when cognitive and motor processes are coupled within a single task and whether these effects are modulated by handedness. Increasing memory load reliably degraded working memory task performance and slowed motor preparation, while core movement execution measures remained largely preserved. Regarding electroencephalography data, parieto-occipital activity increased with load during both the early visual-evoked N1 and the delay period. However, load-related modulation reached a plateau at the 3-disc condition during the delay period only. Posterior-frontal engagement also strengthened as load increased, consistent with demands on attentional control, memory maintenance, and sensorimotor planning. Brain-behavior associations were most robust at a moderate level (2-disc), where contralateral delay activity correlated with both cognitive and motor performance measures. Finally, although handedness exerted selective behavioral effects, it did not modulate load-related parieto-occipital neural activity. Together, these findings demonstrate that a multimodal MoBI approach captures integrated cognitive-motor dynamics during working memory-guided actions, providing a more comprehensive characterization of behavior and underlying neural signatures than either modality alone. This framework offers a translational approach for studying cognitive-motor interactions and their potential disruption in neurological conditions such as Parkinsons disease.

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bioRxiv2025

Longitudinal Exploration of Auditory Sensory-Perceptual Processing in CLN3 Disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): A High-Density Auditory Evoked Potential (AEP) Study.

BackgroundThere is currently limited information about sensory and perceptual abilities across the progression of CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis; Batten disease), a recessively inherited lysosomal storage disorder and a leading cause of childhood neurodegeneration. Clinical symptoms include vision loss, motor impairments, and cognitive challenges, making it difficult to accurately assess neurocognitive and perceptual abilities. Thus, there is a critical need to identify objective biomarkers that can be used to inform disease progression and track treatment response in this population. MethodsThis exploratory study investigates longitudinal changes in auditory sensory perceptual processing in a small sample of individuals with genetically confirmed CLN3 disease (N=4; 3 male) compared to a cross-sectional sample of 60 neurotypical (NT) controls using high-density electroencephalography (EEG). We utilized a duration mismatch negativity (MMN) paradigm, identical to what has been used in our previous cross-sectional study. We examined the auditory evoked potentials (AEPs) of the standard tones across three different stimulus onset asynchrony conditions and examined the N1 and P2 components of the AEP. ResultsWe found age related differences in the amplitudes of the N1 and P2 components in individuals with CLN3 disease relative to NT controls. These amplitude differences were most notable in CLN3 disease when participants were presented with standard tones that had the slowest presentation rate. Specifically, N1 and P2 amplitudes were more negative than NT controls in childhood and adolescence and as CLN3 disease participants aged, the amplitude of the AEPs was greater than controls. Further, a more positive N1 amplitude during the longest stimulus presentation condition was associated with both reduced verbal intelligence and working memory abilities in CLN3 disease participants. ConclusionsOur preliminary findings parallel recently published work in a mouse model of CLN3 disease that showed both sex- and age-dependent disruptions in central auditory processing. Taken together, we demonstrate the utility of auditory EEG measures as a sensitive, objective and translational measure in CLN3 disease that may serve as a potential outcome measure useful in tracking disease progression. Continued work is needed in humans focused on sex-based differences and longitudinal changes of auditory processing in CLN3 disease.

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bioRxiv2025

Disrupted Top-Down Modulation as a Mechanism of Impaired Multisensory Processing in Children with an Autism Spectrum Diagnosis.

Atypical sensory processing is a core feature of autism, particularly when integration across sensory modalities is required. The neural mechanisms underlying these multisensory differences remain unclear. We recorded high-density EEG while autistic children aged 8-13 (AU; n=40), unaffected siblings of autistic children (SIB; n=26), and non-autistic controls (NA; n=36) performed a simple reaction-time task to auditory (A), visual (V), and audiovisual (AV) stimuli. Analyses targeted event-related potentials (ERPs; P1/N1/P2), alpha-band event-related desynchronization (-ERD), and long-range theta-band functional connectivity (weighted phase-lag index, wPLI). Across all unisensory measures (ERPs, -ERD, and connectivity), groups did not differ, indicating broadly comparable unisensory processing. By contrast, multisensory integration (MSI; operationalized for ERPs and -ERD as AV - (A+V)) differed across groups: NA children showed significant ERP MSI over parieto-central sites that was absent in AU and SIB; and -ERD MSI was present in all groups but significantly reduced in AU, with SIB showing an intermediate profile. Connectivity analyses revealed that AV theta-band fronto-parieto-occipital coupling was reduced in autistic relative to non-autistic children, consistent with weaker large-scale coordination during multisensory processing. Together, these results point to a multisensory-specific deficit in autism spanning early sensory encoding, posterior -ERD, and fronto-posterior coupling. The convergence of results supports a mechanistic account of disrupted multisensory influences on sensory processing due to reduced multisensory attentional orientation. Intermediate SIB profiles suggest inherited liability for these neural phenotypes. These results help explain well-documented behavioral MSI differences in autism by linking impaired early enhancement with attenuated top-down control of sensory cortex.

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bioRxiv2025

Processing of Emotional Faces Has Unique Functional and Cytoarchitectural Associations in those with an Autism Spectrum Diagnosis.

Those with an autism spectrum diagnosis (ASD) have been found to process emotional faces differently than other populations. Processing of emotional faces requires engagement of temporal, frontal, occipital, and limbic brain regions. Functional activity has been shown to differ in those with an ASD, particularly in the amygdala, inferior frontal cortex (IFC), and temporal brain regions. However, the consistency and direction of these associations have been inconsistent across studies. Recent findings have demonstrated that measures of neuron density differ in those with an ASD. Some of these regional differences in cytoarchitecture coincide with regions important to emotional facial processing. Therefore, the interaction between cytoarchitecture and functional activity may be important in elucidating unique neurophysiology in ASD. The present study uses diffusion weighted imaging (DWI) and functional magnetic resonance imaging (fMRI) data from the Adolescent Brain Cognitive Developmentsm (ABCD(R)) study to investigate the relationship between cytoarchitecture and functional activity during emotional face processing in those with an ASD. 75 individuals with a reported ASD and 6,396 individuals with no reported diagnosis of an ASD (nASD) were identified. The emotional n-back (EN-Back) task was administered during fMRI acquisition, activating regions of the brain associated with processing emotional faces. Neuron cell body density was positively correlated with functional activation in the left amygdala in the ASD group but not the nASD group. These findings suggest that a unique relationship may exist between neuron cell body density in the left amygdala and functional activity while processing emotional faces in those with an ASD.

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bioRxiv2025

The School Cafeteria Problem: Disrupted Visuospatial Attention During Multisensory Speech-in-Noise Perception in Children with ADHD

BackgroundMany children with attention deficit hyperactivity disorder (ADHD) have difficulty distinguishing speech in crowded scenarios with competing conversations and noise. This can impact learning and community participation. Prior work has implicated audiovisual integration of lip movements with speech sounds as a potential underlying mechanism, but difficulty in accurately deploying spatial attention is an important, often overlooked, factor that may impact the accuracy of speech perception in noisy environments. ObjectiveEvaluate patterns of audiovisual integration and allocation of visuospatial attention during speech processing in a multiple-talker scenario among school-age children with ADHD and typically developing children (TD). MethodsWe recruited 7-12-year-old children with ADHD to participate in an integrated virtual reality and electrophysiologic (EEG) speech-in-noise perception paradigm. In virtual reality, children were asked to press a button whenever a centrally-located target character spoke a target monosyllabic word, while ignoring any words spoken by two flanking distractor characters. We manipulated 1) audiovisual (AV) content by intermixing trials containing either audio, visual, or multisensory AV representations of the three characters and 2) spatial attention demands by including trials with and without interference from the distracting speakers. We measured AV gain in target detection accuracy. Simultaneously, steady-state visual evoked potentials (SSVEP) were continuously recorded via a 128-channel electrode array as an index of visuospatial attention allocation to each speaker. To elicit SSVEP, the target and distractor speakers were tagged with different visual frequency oscillations (23hz and 15hz, respectively). EEG signal-to-noise ratio (SNR) in the corresponding first and second harmonics for those frequency bands was measured over the occipital scalp. ResultsChildren with ADHD showed reduced AV gain relative to TD controls. TD controls also demonstrated more robust SSVEP at 23Hz and 46Hz (target speaker) than at 15Hz (distractor speakers). Compared to TD children, children with ADHD had reduced selective activation in response to the target. As a result, children with ADHD showed more equivalent allocation of visuospatial attention between 23Hz target and 15Hz distractor frequencies. ConclusionsChildren with ADHD demonstrate a reduction in the typical perceptual benefit afforded by exposure to multisensory compared to unisensory speech stimuli, accompanied by substantial differences in the allocation of visuospatial attention to the relevant speaker. Thus, dysregulation of selective visuospatial attention may impair their ability to effectively perceive language in noisy settings.

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bioRxiv2025

Neural oscillatory dynamics reveal altered top-down and integrative mechanisms during face processing in autistic children and unaffected siblings of autistic children

Face processing is fundamental to social communication and has been a major focus of autism research. While event-related potential (ERPs) studies of face processing have produced mixed results, little work has examined neuro-oscillatory dynamics, which may better capture the integrity of underlying networks. To address this gap, EEG was recorded from children aged 8-13 across three groups: autistic (n = 50), non-autistic (n = 38) and siblings of autistic children (n = 26), during a visual oddball task. In a blocked design, participants viewed faces and objects, presented upright and inverted (non-targets), to assess the face inversion effect (the FIE; a larger or earlier N170 to inverted than upright faces), and responded to infrequent shadow versions (targets). Analyses using permutation statistics and linear mixed models focused on non-target stimuli, quantifying face-related ERPs (P1, N170) and oscillatory activity associated with sensory and attentional processing (theta, alpha, gamma). Across groups, faces elicited earlier P1 and larger N170 amplitudes than objects, and showed a FIE. Furthermore, the rightward lateralization of the FIE was reduced for autistic participants. Analyses in the frequency domain revealed greater induced theta for inverted versus upright stimuli and for faces versus objects, revealing face specific effects, and stronger theta for inverted faces for the autistic and sibling groups, suggesting greater cognitive effort in processing these social stimuli. Gamma-band inter-trial phase coherence exhibited face selectivity only in the non-autistic group, pointing to differences in early network synchronization in autistic children relative to their non-autistic peers, whereas alpha event-related desynchronization did not vary by group or category. Altogether, these findings support altered neural synchronization/efficiency for autistic participants and siblings of autistic children, that is specific to face stimuli and seen despite largely typical sensory driven encoding. These data suggest that neural oscillatory assays are more sensitive to face processing differences in autism than broadband ERPs and that these oscillatory assays may be endophenotypic.

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bioRxiv2025

Children with Autism Show Impaired Oculomotor Entrainment to Predictable Stimuli

Individuals with Autism Spectrum Disorder (ASD) show altered synchronization with external events, which may underlie the rigidity and reduced adaptability that characterize the condition. We previously demonstrated that electroencephalography (EEG) recorded from children with ASD reveals impaired neuronal entrainment to predictable visual sequences. Whether similar effects are reflected in other physiological signals remains unclear. Here, we investigated whether eye movement and pupil dilation responses exhibit comparable entrainment differences in ASD. Microsaccades (MS) and pupil diameter were recorded from 31 children with ASD (6-9 years) and 21 age- and IQ-matched typically developing (TD) controls during a task in which four equally spaced visual cues preceded an auditory target. We analyzed modulation of MS release time (MS RT) and pupil response time (pupil RT), along with trial-by-trial variability, as indices of ocular entrainment. Both groups exhibited periodic oculomotor responses to the cues, including phasic MS inhibition and repeated pupil constrictions. In TD children, MS RT and pupil RT increased across cues while their variability decreased, consistent with progressive temporal alignment. These effects were significantly reduced in the ASD group. Oculomotor entrainment measures correlated with EEG inter-trial phase coherence (ITPC) in TD but not ASD children. They also correlated with behavioral response times in both groups, and moderately correlated with autism severity scores. Children with ASD thus showed diminished oculomotor modulation and greater variability in response to predictable stimuli, paralleling earlier EEG findings. These results suggest convergence across physiological systems in indexing impaired processing of predictability in ASD and highlight the promise of multimodal approaches.

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bioRxiv2025

Testing the auditory steady-state response (ASSR) to 40-Hz and 27-Hz click trains in children with autism spectrum disorder and their first-degree biological relatives: A high-density electroencephalographic (EEG) study

MotivationAltered auditory processing likely contributes to core social and attentional impairments in autism spectrum disorder (ASD). The auditory steady-state response (ASSR)-- a neural measure of auditory processing and cortical excitatory-inhibitory balance--has yielded mixed results in ASD. This study uses high density electroencephalography (EEG) to evaluate ASSR in ASD and unaffected siblings to clarify neural mechanisms underlying auditory deficits in autism. MethodsHigh-density 70-channel EEG was recorded in children (8-12 years, IQ >80) with ASD (n=53), typically developing (TD) peers (n=35), and unaffected biological siblings (n=26) during 500-ms binaural click trains (27- and 40-Hz) in an active oddball task. ResultsNo group differences were observed in frequency-following responses (FFR) to 27- or 40-Hz stimuli, although higher 40-Hz power was associated with older age and better behavioral performance in ASD. The broad-band response from 180-250 ms was reduced in ASD for both stimulation frequencies--particularly in the low-frequency (<8 Hz) range--and significantly correlated with IQ and age. Siblings showed intermediate broad-band responses. DiscussionWhile FFRs appeared intact in ASD, we observed reduced broad-band response in the transition period to the steady state FFR, which was specific to low (<8-Hz) frequencies--potentially reflecting reduced synchronization at timescales that correspond with slower, syllabic rhythms ([~]4-8 Hz) occurring in natural speech. Intermediate responses in first-degree relatives suggest that this is related to genetic vulnerability for ASD and highlights its clinical relevance. These findings suggest intact sensory processing in ASD alongside possible top-down auditory feedback deficits, which may serve as heritable neurophysiological markers. Lay AbstractChildren with autism may process sounds differently, which could contribute to challenges with attention and communication. Here, electroencephalography (EEG) measured how the brain responds to rapidly repeating sounds and found that, while basic sound processing was intact, children with autism showed significantly reduced low-frequency responses that may reflect difficulty tracking speech rhythm. Interestingly, unaffected siblings showed an intermediate response, suggesting this may be a heritable marker of neural differences in autism.

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bioRxiv2025

Not Just Noise: Impaired Oscillatory Entrainment Reflects Reduced Temporal Flexibility in Autism

Rhythmic patterns in the environment enhance neural activity, perception, and action. However, natural rhythms are often imprecise, requiring flexible adaptation. In autism Spectrum Disorder (ASD), characterized by cognitive rigidity and atypical use of prior information - favoring immediate sensory input over predictive cues - entrainment to temporally variable input may be reduced at both neural and behavioral levels, though the neural mechanisms remain unclear. Here, we recorded high-density EEG and behavior in adults with ASD (n=20) and neurotypical (NT) controls (n=21) during a visual detection task with four rhythmic structures, parametrically varied from an isochronous fully regular rhythm, to a highly irregular one. Spectral analysis and temporal response function (TRF) models revealed significantly reduced modulation by temporal regularity in ASD, particularly in mildly jittered stimulation streams. Additionally, the coupling between phases of neural oscillations and behavior was diminished in ASD under the jittered conditions, suggesting reduced functional relevance of neural synchronization. Residual spectral power post-stimulation showed lower oscillatory entrainment in ASD, ruling out simple evoked-response explanations. Notably, the degree of neural modulation by temporal regularity was correlated with IQ within the ASD group, suggesting a link between temporal flexibility and individual cognitive profiles. These findings highlight impaired neural entrainment and reduced behavioral modulation by temporal structure in ASD, offering insight into inflexible responses to uncertain, volatile sensory environments. InnovationEntrainment to rhythmic events is reduced in autism, but it remains unclear whether this reflects a general, non-selective deficit in neuro-oscillatory alignment or a selective vulnerability to volatile temporal structures, such as those with embedded jitter. To address this, we recorded cortical activity and behavioral performance as participants with ASD engaged with visual sequences of varying rhythmic regularity, and examined how temporal predictability modulated oscillatory entrainment. By correlating neural entrainment with target detection and clinical profiles, we sought to uncover a key feature of the autistic phenotype: reduced temporal flexibility in adapting to unpredictable sensory environments.

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bioRxiv2025

Associations between symptom severity in Autism and functional neuroimaging measures of audiovisual speech perception.

Individuals on the Autism Spectrum do not benefit from visual articulatory cues when compared to neurotypicals especially under noisy environmental conditions. We hypothesized that this deficit would vary with the severity of Autism related symptoms and assessed this relationship in a behavioral speech in noise task (n = 32) and a functional neuroimaging study (n = 37). We found that Calibrated Symptom Severity Scores (CSS) were associated with poorer audiovisual performance but not performance in the auditory-alone condition indicating that impairments are limited to multisensory information processing. These findings underscore the validity of MS deficits and their potential relevance to the broader symptomatology in ASD. We also found that CSS significantly correlated with the hemodynamic responses to AV stimulation. Here, higher the symptom severity was associated with lower multisensory gain in dorsal speech and language regions. Subsequent exploratory analysis suggested that individuals with ASD may not engage speech motor regions in similar ways to TD individuals. These results differed from findings in our previous study (Ross et al., 2024) where a direct comparison between TD and ASD BOLD effect revealed differences in activation in mostly frontal regions, not associated with the task.

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bioRxiv2025

Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease

CLN3 disease is a prevalent form of Neuronal Ceroid Lipofuscinosis (NCL) caused by inherited mutations in the CLN3 gene, with symptoms such as vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates neurological assessment of brain pathophysiology underlying cognitive decline, while the small number of CLN3 mutation cases in humans hinders the study of sex differences. Building on our recent progress in assessing auditory neurophysiological changes in CLN3 patients, we developed a parallel approach using electroencephalography arrays in Cln3 knockout (Cln3-/-) mice to investigate the longitudinal progression of auditory processing deficits in both sexes. We employed a duration mismatch negativity (MMN) paradigm, similar to that used in our CLN3 patient studies, to assess the automatic detection of pattern changes in a sequence of stimuli. Wild-type mice of both sexes showed robust duration MMN responses when assessed longitudinally in the same subjects from 3 to 9 months of age. In contrast, female Cln3-/- mice developed consistent MMN deficits throughout this age range, while male Cln3-/- mice exhibited MMN deficits at younger ages that were mitigated at older ages. Analyses of auditory brainstem responses indicate that MMN abnormalities in Cln3-/- mice are not due to peripheral hearing loss. Instead, these deficits originate centrally from sex-specific and age-related changes in auditory evoked potentials elicited by standard and deviant stimuli. Our findings reveal a sex-specific progression of central auditory processing deficits in Cln3-/- mice, supporting auditory duration MMN as a translational neurophysiological biomarker for mechanistic studies and therapeutic development. Significance StatementCLN3 disease is an inherited neurodegenerative disorder with progressive decline in cognitive functioning and verbal abilities. The neuropathophysiological mechanisms underlying this decline remain poorly understood, highlighting the urgent need for objective neurological biomarkers to advance mechanistic insights and therapeutic development. Our identification of central auditory processing and change detection deficits in Cln3-/- mice, mirroring findings from our recent studies in CLN3 patients, validates auditory MMN as a translational neurophysiological biomarker bridging pre-clinical and clinical research. Moreover, our discovery of sex-specific, non-linear progression of MMN deficits emphasizes the necessity of developing disease management strategies tailored to each sex. This finding also provides a foundation for investigating both pathogenic and compensatory neural mechanisms to inform the development of individualized treatments.

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