Biology subjects

Molholm, S.

Publications and source records attributed to Molholm, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Multimodal MRI Clustering Reveals an Elevated Free-Water Biotype in Autism with Increased Social Symptoms

Background: Autism spectrum disorder (ASD) is neurobiologically heterogeneous, and group comparisons may mask effects confined to subgroups. We tested whether distinct biotypes exist within ASD using unsupervised clustering of multimodal MRI. Methods: We analyzed 149 participants with ASD and 129 typically developing (TD) controls from the Autism Brain Imaging Data Exchange II (6 sites; age 5 to 64 years). Site-harmonized features comprised free water (FW), tissue anisotropy and diffusivity, diffusion tensor image analysis along the perivascular space (DTI-ALPS), cerebrospinal fluid (CSF) volumes and exploratory resting-state regional homogeneity. ASD participants were clustered with k-means using global (7 features) and regional (17 features) sets, with robustness tested by permutation and two further algorithms. TD participants were projected post hoc to test specificity. A composite imaging score was related to Social Responsiveness Scale (SRS) subscales, symptom severity and IQ using partial correlations with false discovery rate correction. Results: Clustering identified an elevated free-water (EFW) biotype comprising approximately 10% of ASD participants, defined by markedly increased FW (d = +4.91 versus remaining ASD participants), reduced tissue anisotropy, reduced DTI-ALPS and enlarged ventricles. It was recovered across feature sets and algorithms (permutation p < .0001) and departed from TD norms, unlike the remaining ASD participants. The composite score correlated with social-perceptual and communicative SRS subscales, most strongly social awareness (r = +0.253, q = .026), but not with symptom severity or IQ. FW related to social motivation in children and adolescents (r = +0.287, q = .037) but not adults. Limitations: Each person was scanned once, so we cannot tell whether these brain differences cause social difficulties or how they change with age. The subgroup was small, clinical data were incomplete, the sample was mostly male with a wide age range, and the findings await confirmation in an independent group. Free water can reflect inflammation, swelling or tissue loss, so its biological meaning remains uncertain. Conclusions: We identify an ASD subgroup defined by extracellular fluid excess and altered white matter that is associated with greater social difficulties. If replicated, this signature may help stratify autistic individuals in mechanistic studies and clinical trials.

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bioRxiv2026

Revisiting post-stimulus theta activity: evidence for an aperiodic rather than oscillatory origin

The aperiodic, 1/f-like component of electrophysiological activity is increasingly recognized as a meaningful feature of neural function, rather than background noise. In parallel, many EEG studies report transient changes in oscillatory power following stimulus onset and interpret these effects as signatures of attention, salience, or cognitive control. However, such conclusions usually rely on baseline normalization procedures that assume aperiodic activity remains stable from pre-to post-stimulus periods. Using high-density EEG recordings from typically developing children, we tested this assumption in two paradigms: an audiovisual simple reaction-time task (n = 36) and a visual oddball task (n = 38). For each task, conventional spectral analyses were compared with analyses that explicitly modeled and removed the aperiodic component in both pre- and post-stimulus windows. Across tasks, stimulus onset was associated with robust increases in aperiodic exponent and offset, indicating systematic changes in the 1/f component of the spectrum. In the audiovisual task, these changes were modality-specific, with central, parieto-occipital, or combined topographies depending on stimulus type. These effects were reduced but remained significant after ERP removal, indicating that they were not fully explained by phase-locked activity. Critically, once aperiodic activity was accounted for, the apparent post-stimulus increase in theta power was largely abolished in both tasks, including the canonical fronto-central theta enhancement to infrequent targets in the oddball paradigm. The conventional method also overestimated the magnitude of beta desynchronization, particularly in the induced (ERP-removed) signal. The apparent gamma desynchronization detected by conventional analyses was reversed after aperiodic correction, revealing either synchronization or no change, indicating that it reflects a spurious consequence of spectral slope steepening rather than a true suppression of gamma oscillatory activity. In contrast, alpha desynchronization remained robust after aperiodic correction and was in fact enhanced, suggesting it reflects genuine oscillatory suppression. Together, these findings indicate that a substantial portion of conventional time-frequency effects, particularly apparent theta synchronization, may reflect changes in aperiodic activity in response to stimulation rather than genuine periodic oscillations, challenging core assumptions of conventional time-frequency analyses. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/732609v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1d25f43org.highwire.dtl.DTLVardef@6c476aorg.highwire.dtl.DTLVardef@c4a02aorg.highwire.dtl.DTLVardef@ef417d_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

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bioRxiv2026

Reduced flexibility in predictive tuning and contextual adaptation in autism: an EEG and behavioral study.

The brain generates predictions to prepare for upcoming events. Because the environment is not perfectly predictable, the brain also estimates the certainty of these predictions and adjusts preparatory processes accordingly. Given that autistic individuals often resist even small changes to everyday routines, we hypothesized altered tuning of prediction certainty in autism. To test this, EEG was recorded from adolescents and young autistic adults (n = 20) and from age- and IQ-matched non-autistic adults (n = 19) during a probabilistic cued target identification task during which cue validity was systematically varied across four levels: 100%, 84%, 67%, and 33%. Participants were not informed of the cue-target validity nor when it changed. We focused on two neural signatures of anticipatory readiness, contingent negative variation (CNV) and alpha-band event-related desynchronization (-ERD), and one of cognitive updating: the P3 to targets and to invalid (e.g., a non-target in place of the target) stimuli. Across groups, preparatory activity increased as contextual certainty decreased, with larger CNV amplitudes and stronger -ERD preceding targets in lower-probability contexts, suggesting enhanced preparatory engagement under greater uncertainty. Furthermore, larger CNV amplitudes predicted faster reaction times, indicating functionally significant anticipatory dynamics. However, modulation of both neural preparation and response times as a function of cue-target probability was significantly reduced in the autistic group. In addition, autistic participants showed diminished probability-dependent modulation of the P3b to both targets and invalid stimuli, and coupling between anticipatory activity (CNV) and subsequent updating (P3b) was observed in non-autistic participants whereas it was absent in autism. Together, these findings suggest that while predictive mechanisms are present in autism, anticipatory processes are less flexibly tuned to contextual uncertainty and less effectively linked to subsequent cognitive updating. This reduced adaptability may reflect difficulty adjusting internal predictive models to changing environmental contingencies, potentially contributing to core features of autism such as resistance to change and insistence on sameness. HighlightsO_LIAnticipatory brain mechanisms (CNV and alpha desynchronization) are present in autism and are behaviorally relevant, predicting faster responses. C_LIO_LIAutistic individuals exhibit reduced modulation of anticipatory CNV and alpha activity as a function of cue-target validity. C_LIO_LIP3b responses to both targets and invalid stimuli show diminished sensitivity to contextual probability in autism, consistent with altered prior updating. C_LIO_LIThe link between anticipatory activity and cognitive updating (i.e., CNV to P3b) is disrupted in autism. C_LIO_LIP3a amplitude to invalid stimuli is reduced in autism, suggesting diminished engagement of violation-sensitive processes. C_LIO_LITogether, findings point to less flexible tuning of predictive mechanisms and reduced adaptation to contextual uncertainty in autism. 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

Natural scene segmentation dynamics reveal iterative Bayesian inference

The visual system operates by segmenting visual inputs into distinct perceptual objects. Segmentation is dynamic, as revealed by the tempo of perceptual choices and neural activity in visual cortex. Dynamics for natural stimuli however, are poorly understood because natural scene segmentation is ambiguous and subjective. We measured subjective human segmentation maps for natural images using an innovative paradigm, and uncovered richer spatiotemporal dynamics than predicted by current theories of segmentation. To explain these dynamics, we introduced Iterative Bayesian Inference algorithms for segmentation that iteratively integrate visual inputs with the prior expectation that objects are spatially compact. When visual inputs were consistent with such a spatial prior, iterative inference was faster. This predicted relationship between spatial prior and inferential dynamics was evident in our data, and correctly reflected each individual participants spatial biases. We conclude that iterative Bayesian inference sets the tempo for a fundamental function of natural vision.

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bioRxiv2025

A Multimodal Framework for Understanding Perceptual Segmentation of Natural Scenes In Autism

Understanding how individuals organize complex natural scenes into perceptual segments is essential for explaining both typical and atypical sensory processing. In Autism Spectrum Disorder (ASD), differences in visual segmentation are widely documented. However, existing paradigms often rely on simplified stimuli and do not capture the dynamic, naturalistic processes underlying real world scene segmentation. To overcome those limitations, in this work we present a novel, multimodal experimental framework. The framework combines precisely timed, trial-based perceptual measurements with electroencephalography (EEG) to examine how neural activity aligns temporally with segmentation decisions, and with eye-tracking to examine visual exploration strategies and attention allocation. To demonstrate the framework, we report basic characterization results from a pilot study. Neurotypical (NT) participants and participants with ASD aged 16 years and above viewed natural scenes and textures and indicated whether two cued image regions belonged to the same or different perceptual segments. Each trial used a different pair of cues, and responses across trials enabled the estimation of subjectively perceived segmentation maps and the associated uncertainty. Both cohorts performed the task successfully and produced interpretable segmentation maps. Analysis of reaction time distributions, gaze profiles, and trial-aligned neural responses give us a window into cohort differences and the opportunity to study individual heterogeneity. Together, these findings establish a reproducible method for studying the temporal and spatial components of natural scene segmentation and illustrate that meaningful behavioral and neural distinctions in ASD may be studied with this approach. This framework provides a methodological bridge between controlled experimental stimuli and real-world perception in both neurotypical and neurodivergent populations.

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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

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

Multisensory attenuation of the pupil light response in autistic and non-autistic children

Autonomic responses to sensory stimuli are altered in autism, yet little is known about how multisensory input modulates these responses. This study examined whether auditory stimuli affect the pupil light reflex (PLR), a parasympathetically driven response to light, in autistic and non-autistic children. Pupillometry was used to measure responses to visual-only (V), auditory-only (A), and audiovisual (AV) stimuli in 72 children aged 6-14 years (34 non-autistic, 38 autistic). We hypothesized that auditory input would attenuate pupil constriction in non-autistic children and that this cross-modal modulation might differ in autism, reflecting altered sensory-autonomic functioning. Across groups, results revealed a consistent pattern: auditory stimuli elicited pupil dilation, visual stimuli evoked constriction, and simultaneous audiovisual stimuli led to attenuated constriction relative to visual-only trials. This attenuation lends support to prior findings of multisensory attenuation of the PLR. Time-binned analysis revealed a group effect during the 500-1000 ms post-stimulus window: autistic children showed significantly more positive baseline-corrected pupil responses across conditions (i.e., less constriction in V/AV and greater dilation in A), suggesting group differences in the dynamic trajectory of the pupil response. Contrary to expectations, autistic and non-autistic children did not differ significantly on peak constriction or constriction latency within visual conditions. Findings support the presence of cross-modal modulation of the PLR in both autistic and non-autistic children and suggest that auditory signals influence early-stage visual-autonomic processing similarly across groups. Pupillometry may provide a promising, noninvasive tool for probing sensory-autonomic interactions in autism. Future studies with paradigms optimized for pupil measurement may reveal more nuanced group differences and clarify links to real-world sensory challenges.

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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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bioRxiv2024

Neural Mechanisms of Intersensory Switching: Evidence for Delayed Sensory Processing and Increased Cognitive Effort

Intersensory switching (IS), the ability to shift attention between different sensory systems, is essential for cognitive flexibility, yet leads to slower responses compared to repeating the same sensory modality. The underlying neural mechanisms of IS remain largely unknown. In this study, high-density EEG was used to investigate these mechanisms in healthy adults (n=53) performing a speeded reaction time (RT) task involving visual and auditory stimuli. Trials were categorized as Repeat (same preceding modality) or Switch (different preceding modality). Switch trials showed slower RTs and delayed sensory responses (N1 and P2 components). Furthermore, across both Repeat and Switch trials, RT correlated with the latency of these neural responses. Additionally, lower alpha-band inter-trial phase coherence (ITPC) in primary sensory regions was noted for Switch compared to Repeat trials, suggesting reduced efficiency of sensory processing. Greater induced theta activity over fronto-central scalp regions in Switch trials suggested increased cognitive control demands, potentially involving the anterior cingulate cortex (ACC). These findings reveal that IS is characterized by delayed sensory processing and heightened cognitive load, supporting a model where prior stimulus primes the sensory cortex for faster processing in Repeat trials, while Switch trials demand more cognitive resources for adjustment. The similarity of effects across both auditory and visual sensory modalities suggests that IS effects represent core features of sensory processing, potentially reflecting a fundamental, modality-independent mechanism of attentional switching across sensory domains.

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bioRxiv2024

Intact Somatosensory Temporal Sensitivity in Adults on the Autism Spectrum: A High-Density Electrophysiological Mapping Study Using the Mismatch Negativity (MMN) Sensory Memory Paradigm.

Atypical reactivity to somatosensory inputs is common in autism spectrum disorder and carries considerable impact on downstream social communication and quality of life. While behavioral and survey work have established differences in the perception of somatosensory information, little has been done to elucidate the underlying neurophysiological processes that drive these characteristics. Here, we implemented a duration-based somatosensory mismatch negativity paradigm to examine the role of temporal sensitivity and sensory memory in the processing of vibrotactile information in autistic (n=30) and neurotypical (n=30) adults. To capture the variability in responses between groups across a range of duration discrepancies, we compared the electrophysiological responses to frequent standard vibrations (100 ms) and four infrequent deviant vibrations (115, 130, 145, and 160 ms). The same stimuli were used in a follow-up behavioral task to determine active detection of the infrequent vibrations. We found no differences between the two groups with regard to discrimination between standard and deviant vibrations, demonstrating comparable neurologic and behavioral temporal somatosensory perception. However, exploratory analyses yielded subtle differences in amplitude at the N1 and P220 time points. Together, these results indicate that the temporal mechanisms of somatosensory discrimination are conserved in adults on the autism spectrum, though more general somatosensory processing may be affected. We discuss these findings in the broader context of the MMN literature in autism, as well as the potential role of cortical maturity in somatosensory mechanisms.

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bioRxiv2024

It's all in the timing: Delayed feedback in autism may weaken predictive mechanisms during contour integration

Humans rely on predictive mechanisms during visual processing to efficiently resolve incomplete or ambiguous sensory signals. While initial low-level sensory data are conveyed by feedforward connections, feedback connections are believed to shape sensory processing through conveyance of statistical predictions based on prior exposure to stimulus configurations. Individuals with autism spectrum disorder (ASD) show biases in stimulus processing toward parts rather than wholes, suggesting their sensory processing may be less shaped by statistical predictions acquired through prior exposure to global stimulus properties. Investigations of illusory contour (IC) processing in neurotypical (NT) adults have established a well-tested marker of contour integration characterized by a robust modulation of the visually evoked potential (VEP) - the IC-effect - that occurs over lateral occipital scalp during the timeframe of the N1 component. Converging evidence strongly supports the notion that this IC-effect indexes a signal with significant feedback contributions. Using high-density VEPs, we compared the IC-effect in 6-17-year-old children with ASD (n=32) or NT development (n=53). Both groups of children generated an IC-effect that was equivalent in amplitude. However, the IC-effect notably onset 21ms later in ASD, even though timing of initial VEP afference was identical across groups. This suggests that feedforward information predominated during perceptual processing for 15% longer in ASD compared to NT children. This delay in the feedback dependent IC-effect, in the context of known developmental differences between feedforward and feedback fibers, suggests a potential pathophysiological mechanism of visual processing in ASD, whereby ongoing stimulus processing is less shaped by statistical prediction mechanisms. SIGNIFICANCE STATEMENTChildren with autism often present with an atypical visual perceptual style that emphasizes parts or details over the whole. Using electroencephalography (EEG), this study identifies delays in the visual feedback from higher order sensory brain areas to primary sensory regions. Because this type of visual feedback is thought to carry information about prior sensory experiences, individuals with autism may have difficulty efficiently using prior experience and predictions to help make sense of incoming new visual information. This provides empirical neural evidence to support theories of disrupted sensory perception mechanisms in autism.

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bioRxiv2023

Pre-attentive representation of prediction certainty in autism: A mismatch negativity (MMN) study

According to predictive processing theories of perception, the brain generates predictions to prepare for sensory input, and calibrates certainty of predictions based on their likelihood. When an input doesnt match the prediction, an error signal leads to updating of the predictive model. Prior research suggests altered prediction certainty in autism, but predictive processing occurs across the cortical hierarchy, and the stage(s) of processing where prediction certainty breaks down is unknown. We therefore tested the integrity of prediction certainty in autism at pre-attentive and relatively automatic processing stages using the pre-attentive Mismatch Negativity (MMN) brain response. The MMN occurs in response to a "deviant" presented in a stream of "standards" and is measured while the participant performs an orthogonal task. Most critically, MMN amplitude typically varies with the level of certainty associated with the prediction. We recorded high-density EEG while presenting adolescents and young adults with and without autism with repetitive tones every half second (the standard) interspersed with infrequent pitch and inter-stimulus-interval (ISI) deviants. Pitch and ISI deviant probabilities were manipulated at 4, 8, or 16% within a block of trials to test whether MMN amplitude varied in a typical manner with respect to probability. For both groups, Pitch-MMN amplitude increased as the probability of deviance decreased. Unexpectedly, ISI-MMN amplitude did not reliably vary by probability in either group. Our Pitch-MMN findings suggest intact neural representation of pre-attentive prediction certainty in autism, addressing a critical knowledge gap in autism research. The implications of these findings are considered. LAY SUMMARYOur brains are always trying to predict what will happen next. For example, when you open your utensil drawer, it would be surprising to see books because your brain expected to see utensils. In our study, we looked at whether the brains of autistic individuals automatically and accurately recognize when something unexpected happens. Results showed similar brain patterns in individuals with and without autism, suggesting that responses to prediction violations are generated in a typical manner during early cortical information processing.

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bioRxiv2023

Response inhibition and error-monitoring in cystinosis (CTNS gene mutations): Behavioral and electrophysiological evidence of a diverse set of difficulties

Cystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function. Behaviorally, some deficits in executive function have been noted in this population, but the underlying neural processes are not understood. Using standardized cognitive assessments and a Go/No-Go response inhibition task in conjunction with high-density electrophysiological recordings (EEG), we sought to investigate the behavioral and neural dynamics of inhibition of a prepotent response and of error monitoring (critical components of executive function) in individuals with cystinosis, when compared to age-matched controls. Thirty-seven individuals diagnosed with cystinosis (7-36 years old, 24 women) and 45 age-matched controls (27 women) participated in this study. Analyses focused on N2 and P3 No-Go responses and error-related positivity (Pe). Atypical inhibitory processing was shown behaviorally. Electrophysiological differences were additionally found between the groups, with individuals with cystinosis showing larger No-Go P3s. Error-monitoring was likewise different between the groups, with those with cystinosis showing reduced Pe amplitudes.

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bioRxiv2023

Event-related potential (ERP) evidence of early visual processing differences in cystinosis

Cystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function. Behavioral difficulties have been reported in cystinosis in the visual and visual-processing domain. Very little is known, however, about how the brains of people living with cystinosis process visual information, although cysteamine accumulation in the retina is a prominent feature of cystinosis. Here, electrophysiology was recorded during a Go/No-Go task to investigate early visual processing in cystinosis, compared to an age-matched control group. Analyses focused on early stages of cortical visual processing. The groups differed in their initial cortical response, with individuals with cystinosis exhibiting a significantly larger visual evoked potential (VEP) in the 130 to 150 ms time window. The timing and topography of this response suggested an enhanced P1 in cystinosis that could be the result of cortical hyperexcitability and/or differences in attentional engagement and explain, at least partially, the visual and visual-spatial difficulties described in this population. The groups also differed in the associations between neural responses and verbal abilities: While controls with higher IQ scores presented larger neural responses, that relationship was not observed in cystinosis.

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