Search

Abstract Background In the search for objective tools to quantify neural function in Rett Syndrome (RTT), which are crucial in the evaluation of therapeutic efficacy in clinical trials, recordings of sensory-perceptual functioning using event-related potential (ERP) approaches have emerged as potentially powerful tools. Considerable work points to highly anomalous auditory evoked potentials (AEPs) in RTT. However, an assumption of the typical signal-averaging method used to derive these measures is “stationarity” of the underlying responses – i.e. neural responses to each input are highly stereotyped. An alternate possibility is that responses to repeated stimuli are highly variable in RTT. If so, this will significantly impact the validity of assumptions about underlying neural dysfunction, and likely lead to overestimation of underlying neuropathology. To assess this possibility, analyses at the single-trial level assessing signal-to-noise ratios (SNR), inter-trial variability (ITV) and inter-trial phase coherence (ITPC) are necessary. Methods AEPs were recorded to simple 100 Hz tones from 18 RTT and 27 age-matched controls (Ages: 6–22 years). We applied standard AEP averaging, as well as measures of neuronal reliability at the single-trial level (i.e. SNR, ITV, ITPC). To separate signal-carrying components from non-neural noise sources, we also applied a denoising source separation (DSS) algorithm and then repeated the reliability measures. Results Substantially increased ITV, lower SNRs, and reduced ITPC were observed in auditory responses of RTT participants, supporting a “neural unreliability” account. Application of the DSS technique made it clear that non-neural noise sources contribute to overestimation of the extent of processing deficits in RTT. Post-DSS, ITV measures were substantially reduced, so much so that pre-DSS ITV differences between RTT and TD populations were no longer detected. In the case of SNR and ITPC, DSS substantially improved these estimates in the RTT population, but robust differences between RTT and TD were still fully evident. Conclusions To accurately represent the degree of neural dysfunction in RTT using the ERP technique, a consideration of response reliability at the single-trial level is highly advised. Non-neural sources of noise lead to overestimation of the degree of pathological processing in RTT, and denoising source separation techniques during signal processing substantially ameliorate this issue.

Abstract Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource’s (ClinGen’s) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen’s BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.

Abstract We describe a multidisciplinary teamwork approach known as “Operation IDD Gene Team” developed by the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK IDDRC) at the Albert Einstein College of Medicine. This initiative brings families affected by rare genetic diseases that cause intellectual and developmental disability together with physicians, basic scientists, and their trainees. At team meetings, family members share their child’s medical and personal history, physicians describe the broader clinical consequences of the condition, and scientists provide accessible tutorials focused on the fundamental biology of relevant genes. When appropriate, possible treatment approaches are also discussed. The outcomes of team meetings have been overwhelmingly positive, with families not only expressing deep gratitude, but also becoming empowered to establish foundations dedicated to their child’s specific condition. Physicians, and in particular the scientists and their trainees, have gained a deeper understanding of challenges faced by affected families, broadening their perspective on how their research can extend beyond the laboratory. Remarkably, research by the scientists following the Gene Team meetings have often included focus on the actual gene variants exhibited by the participating children. As these investigations progress and newly created foundations expand their efforts, national as well as international collaborations are forged. These developments emphasize the importance of rare diseases as windows into previously unexplored molecular and cellular processes, which can offer fresh insights into both normal function as well as more common diseases. Elucidating the mechanisms of and treatments for rare and ultra-rare diseases thus has benefits for all involved—families, physicians, and scientists and their trainees, as well as the broader medical community. While the RFK IDDRC’s Operation IDD Gene Team program has focused on intellectual disabilities affecting children, we believe it has the potential to be applied to rare genetic diseases impacting individuals of any age and encompassing a wide variety of developmental disorders affecting multiple organ systems.

BackgroundProgressive difficulty in performing everyday functional activities is a key diagnostic feature of dementia syndromes. However, not much is known about the neural signature of functional decline, particularly during the very early stages of dementia. Early intervention before overt impairment is observed offers the best hope of reducing the burdens of Alzheimer disease (AD) and other dementias. However, to justify early intervention, those at risk need to be detected earlier and more accurately. The decline in complex daily function (CdF) such as managing medications has been reported to precede impairment in basic activities of daily living (eg, eating and dressing). ObjectiveOur goal is to establish the neural signature of decline in CdF during the preclinical dementia period. MethodsGait is central to many CdF and community-based activities. Hence, to elucidate the neural signature of CdF, we validated a novel electroencephalographic approach to measuring gait-related brain activation while participants perform complex gait-based functional tasks. We hypothesize that dementia-related pathology during the preclinical period activates a unique gait-related electroencephalographic (grEEG) pattern that predicts a subsequent decline in CdF. ResultsWe provide preliminary findings showing that older adults reporting CdF limitations can be characterized by a unique gait-related neural signature: weaker sensorimotor and stronger motor control activation. This subsample also had smaller brain volume and white matter hyperintensities in regions affected early by dementia and engaged in less physical exercise. We propose a prospective observational cohort study in cognitively unimpaired older adults with and without subclinical AD (plasma amyloid-β) and vascular (white matter hyperintensities) pathologies. We aim to (1) establish the unique grEEG activation as the neural signature and predictor of decline in CdF during the preclinical dementia period; (2) determine associations between dementia-related pathologies and incidence of the neural signature of CdF; and (3) establish associations between a dementia risk factor, physical inactivity, and the neural signature of CdF. ConclusionsBy establishing the clinical relevance and biological basis of the neural signature of CdF decline, we aim to improve prediction during the preclinical stages of ADs and other dementias. Our approach has important research and translational implications because grEEG protocols are relatively inexpensive and portable, and predicting CdF decline may have real-world benefits. International Registered Report Identifier (IRRID)DERR1-10.2196/56726

Abstract Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome (ANDS), a rare genetic disease characterized by autism spectrum disorder (ASD), attention deficit/hyperactivity disorder, and speech and motor deficits. The ANKS1B gene encodes for AIDA-1, a protein that is enriched at neuronal synapses and regulates synaptic plasticity. Here we report an unexpected role for oligodendroglial deficits in ANDS pathophysiology. We show that Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function, and recapitulate white matter abnormalities observed in ANDS patients. Selective loss of Anks1b from the oligodendrocyte lineage, but not from neuronal populations, leads to deficits in social preference and sensory reactivity previously observed in a brain-wide Anks1b haploinsufficiency model. Furthermore, we find that clemastine, an antihistamine shown to increase oligodendrocyte precursor cell maturation and central nervous system myelination, rescues deficits in social preference in 7-month-old Anks1b-deficient mice. Our work shows that deficits in social behaviors present in ANDS may originate from abnormal Rac1 activity within oligodendrocytes.

Abstract Background Cystinosis, a rare lysosomal storage disease caused by mutations in the CTNS gene, is characterized by cystine crystallization and accumulation within multiple tissues, including kidney and brain. Its impact on neural function appears mild relative to its effects on other organs during early disease, but since therapeutic advances have led to substantially increased life expectancy, neurological implications are of increasing interest, necessitating deeper understanding of the impact of cystinosis on neurocognitive function. Behavioral difficulties have been reported in cystinosis in the visual domain. Very little is known, however, about how the brains of people living with cystinosis process visual information. This is especially interesting given that cystine accumulation in the cornea and posterior ocular structures is a hallmark of cystinosis. Methods Here, high-density scalp electrophysiology was recorded to visual stimuli (during a Go/No-Go task) to investigate visual processing in individuals with cystinosis, compared to age-matched controls. Analyses focused on early stages of cortical visual processing. Results The groups differed in their initial cortical response, with individuals with cystinosis exhibiting a significantly larger visual evoked potential (VEP) in the 130–150 ms time window. 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. Conclusions The enlarged VEP in cystinosis 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.

Abstract Background Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these “supra-modal” traits in the autistic population. Methods Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3–18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a “general response pattern” factor for each supra-modal construct and determine the added value of “modality-specific response pattern” scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. Results All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ωH = .800) but not a supra-modal HYPO construct (ωH = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ωH = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations). Limitations Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many “real-world” sensory experiences. Conclusion Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.

Abstract 22q11.2 deletion syndrome (22q11.2DS) is a multisystemic disorder characterized by a wide range of clinical features, ranging from life-threatening to less severe conditions. One-third of individuals with the deletion live with mild to moderate intellectual disability; approximately 60% meet criteria for at least one psychiatric condition. 22q11.2DS has become an important model for several medical, developmental, and psychiatric disorders. We have been particularly interested in understanding the risk for psychosis in this population: Approximately 30% of the individuals with the deletion go on to develop schizophrenia. The characterization of cognitive and neural differences between those individuals who develop schizophrenia and those who do not, despite being at genetic risk, holds important promise in what pertains to the clarification of paths to disease and to the development of tools for early identification and intervention. Here, we review our previous event-related potential (ERP) findings as potential markers for 22q11.2DS and the associated risk for psychosis, while discussing others’ work. We focus on auditory processing (auditory-evoked potentials, auditory adaptation, and auditory sensory memory), visual processing (visual-evoked potentials and visual adaptation), and inhibition and error monitoring. The findings discussed suggest basic mechanistic and disease process effects on neural processing in 22q11.2DS that are present in both early sensory and later cognitive processing, with possible implications for phenotype. In early sensory processes, both during auditory and visual processing, two mechanisms that impact neural responses in opposite ways seem to coexist—one related to the deletion, which increases brain responses; another linked to psychosis, decreasing neural activity. Later, higher-order cognitive processes may be equally relevant as markers for psychosis. More specifically, we argue that components related to error monitoring may hold particular promise in the study of risk for schizophrenia in the general population.

Abstract Background Atypical auditory cortical processing is consistently found in scalp electrophysiological and magnetoencephalographic studies of Autism Spectrum Disorder (ASD), and may provide a marker of neuropathological brain development. However, the relationship between atypical cortical processing of auditory information and adaptive behavior in ASD is not yet well understood. Methods We sought to test the hypothesis that early (100-175 ms) auditory processing in ASD is related to everyday adaptive behavior through the examination of auditory event-related potentials (AEPs) in response to simple tones and Vineland Adaptive Behavior Scales in a large cohort of children with ASD (N = 84), aged 6–17, and in age- and IQ- matched neurotypically (NT) developing controls (N = 132). Results Statistical analyses revealed significant group differences in early AEPs over temporal scalp regions (150-175 ms), and the expected rightward lateralization of the AEP (100-125 ms and 150-175 ms) to tonal stimuli in both groups. Lateralization of the AEP (150-175 ms) was significantly associated with adaptive functioning in the socialization domain. Conclusions These results lend support to the hypothesis that atypical processing of sensory information is related to everyday adaptive behavior in autism.

Autism Spectrum Disorder (ASD) is characterized by rigidity of routines and restricted interests, and atypical social communication and interaction. Recent evidence for altered synchronization of neuro-oscillatory brain activity with regularities in the environment and of altered peripheral nervous system function in ASD present promising novel directions for studying pathophysiology and its relationship to ASD clinical phenotype. Human cognition and action are significantly influenced by physiological rhythmic processes that are generated by both the central nervous system (CNS) and the autonomic nervous system (ANS). Normally, perception occurs in a dynamic context, where brain oscillations and autonomic signals synchronize with external events to optimally receive temporally predictable rhythmic information, leading to improved performance. The recent findings on the time-sensitive coupling between the brain and the periphery in effective perception and successful social interactions in typically developed highlight studying the interactions within the brain–body-environment triad as a critical direction in the study of ASD. Here we offer a novel perspective of autism as a case where the temporal dynamics of brain–body-environment coupling is impaired. We present evidence from the literature to support the idea that in autism the nervous system fails to operate in an adaptive manner to synchronize with temporally predictable events in the environment to optimize perception and behavior. This framework could potentially lead to novel biomarkers of hallmark deficits in ASD such as cognitive rigidity and altered social interaction.

In everyday life, the brain processes a multitude of stimuli from the surrounding environment, requiring the integration of information from different sensory modalities to form a coherent perception. This process, known as multisensory integration, enhances the brain’s response to redundant congruent sensory cues. However, it is equally important for the brain to segregate sensory inputs from distinct events, to interact with and correctly perceive the multisensory environment. This problem the brain must face, known as the causal inference problem, is strictly related to multisensory integration. It is widely recognized that the ability to integrate information from different senses emerges during the developmental period, as a function of our experience with multisensory stimuli. Consequently, multisensory integrative abilities are altered in individuals who have atypical experiences with cross-modal cues, such as those on the autistic spectrum. However, no research has been conducted on the developmental trajectories of causal inference and its relationship with experience thus far. Here, we used a neuro-computational model to simulate and investigate the development of causal inference in both typically developing children and those in the autistic spectrum. Our results indicate that higher exposure to cross-modal cues accelerates the acquisition of causal inference abilities, and a minimum level of experience with multisensory stimuli is required to develop fully mature behavior. We then simulated the altered developmental trajectory of causal inference in individuals with autism by assuming reduced multisensory experience during training. The results suggest that causal inference reaches complete maturity much later in these individuals compared to neurotypical individuals. Furthermore, we discuss the underlying neural mechanisms and network architecture involved in these processes, highlighting that the development of causal inference follows the evolution of the mechanisms subserving multisensory integration. Overall, this study provides a computational framework, unifying causal inference and multisensory integration, which allows us to suggest neural mechanisms and provide testable predictions about the development of such abilities in typically developed and autistic children.

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 neuro-markers 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.ConclusionOf the three studies to date of saccade adaptation in ASD, none have shown deficits in saccade adaptation that are sufficient to generalize to the whole or a subgroup of the ASD population. 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.

Abstract Background The COVID-19 pandemic impacted nearly all facets of our daily lives, and clinical research was no exception. Here, we discuss the impact of the pandemic on our ongoing, three-arm randomized controlled trial (RCT) Sensory Integration Therapy (SIT) in Autism: Mechanisms and Effectiveness (NCT02536365), which investigates the immediate and sustained utility of SIT to strengthen functional daily-living skills and minimize the presence of maladaptive sensory behaviors in autistic children. Main text In this text, we detail how we navigated the unique challenges that the pandemic brought forth between the years 2020 and 2021, including the need to rapidly adjust our study protocol, recruitment strategy, and in-person assessment battery to allow for virtual recruitment and data collection. We further detail how we triaged participants and allocated limited resources to best preserve our primary outcome measures while prioritizing the safety of our participants and study team. We specifically note the importance of open and consistent communication with all participating families throughout the pandemic in ensuring all our protocol adjustments were successfully implemented. Conclusions Though the COVID-19 pandemic resulted in an unprecedented interruption to in-person clinical research, clinical trials have always been and will continue to be at risk for unforeseen interruptions, whether from world events or participants’ personal circumstances. By presenting our steps to preserving this RCT throughout the pandemic, we offer suggestions for successfully managing unexpected interruptions to research. Ideally, by taking these into account, future RCTs may be increasingly prepared to minimize the impact of these potential interruptions to research.

Abstract Background Biological motion imparts rich information related to the movement, actions, intentions and affective state of others, which can provide foundational support for various aspects of social cognition and behavior. Given that atypical social communication and cognition are hallmark symptoms of autism spectrum disorder (ASD), many have theorized that a potential source of this deficit may lie in dysfunctional neural mechanisms of biological motion processing. Synthesis of existing literature provides some support for biological motion processing deficits in autism spectrum disorder, although high study heterogeneity and inconsistent findings complicate interpretation. Here, we attempted to reconcile some of this residual controversy by investigating a possible modulating role for attention in biological motion processing in ASD. Methods We employed high-density electroencephalographic recordings while participants observed point-light displays of upright, inverted and scrambled biological motion under two task conditions to explore spatiotemporal dynamics of intentional and unintentional biological motion processing in children and adolescents with ASD (n = 27), comparing them to a control cohort of neurotypical (NT) participants (n = 35). Results Behaviorally, ASD participants were able to discriminate biological motion with similar accuracy to NT controls. However, electrophysiologic investigation revealed reduced automatic selective processing of upright biologic versus scrambled motion stimuli in ASD relative to NT individuals, which was ameliorated when task demands required explicit attention to biological motion. Additionally, we observed distinctive patterns of covariance between visual potentials evoked by biological motion and functional social ability, such that Vineland Adaptive Behavior Scale-Socialization domain scores were differentially associated with biological motion processing in the N1 period in the ASD but not the NT group. Limitations The cross-sectional design of this study does not allow us to definitively answer the question of whether developmental differences in attention to biological motion cause disruption in social communication, and the sample was limited to children with average or above cognitive ability. Conclusions Together, these data suggest that individuals with ASD are able to discriminate, with explicit attention, biological from non-biological motion but demonstrate diminished automatic neural specificity for biological motion processing, which may have cascading implications for the development of higher-order social cognition.

Crosse et al. study a cohort of 364 participants with autism spectrum disorders (ASD) and matched controls, and show that deficits in multisensory processing observed in high-functioning children and teenagers with ASD are not evident in adults with the disorder. Using computational modelling they go on to demonstrate that there is a delayed transition of multisensory processing from a default state of competition to one of facilitation in ASD, as well as differences in sensory weighting and the ability to switch between sensory modalities, which sheds light on the interplay among sensory systems that differ in ASD individuals.

Abstract We investigated visual processing and adaptation in 22q11.2 deletion syndrome (22q11.2DS), a condition characterized by an increased risk for schizophrenia. Visual processing differences have been described in schizophrenia but remain understudied early in the disease course. Electrophysiology was recorded during a visual adaptation task with different interstimulus intervals to investigate visual processing and adaptation in 22q11.2DS (with (22q+) and without (22q−) psychotic symptoms), compared to control and idiopathic schizophrenia groups. Analyses focused on early windows of visual processing. While increased amplitudes were observed in 22q11.2DS in an earlier time window (90–140 ms), decreased responses were seen later (165–205 ms) in schizophrenia and 22q+. 22q11.2DS, and particularly 22q−, presented increased adaptation effects. We argue that while amplitude and adaptation in the earlier time window may reflect specific neurogenetic aspects associated with a deletion in chromosome 22, amplitude in the later window may be a marker of the presence of psychosis and/or of its chronicity/severity.

This fMRI study investigated the effect of seeing articulatory movements of a speaker while listening to a naturalistic narrative stimulus. It had the goal to identify regions of the language network showing multisensory enhancement under synchronous audiovisual conditions. We expected this enhancement to emerge in regions known to underlie the integration of auditory and visual information such as the posterior superior temporal gyrus as well as parts of the broader language network, including the semantic system. To this end we presented 53 participants with a continuous narration of a story in auditory alone, visual alone, and both synchronous and asynchronous audiovisual speech conditions while recording brain activity using BOLD fMRI. We found multisensory enhancement in an extensive network of regions underlying multisensory integration and parts of the semantic network as well as extralinguistic regions not usually associated with multisensory integration, namely the primary visual cortex and the bilateral amygdala. Analysis also revealed involvement of thalamic brain regions along the visual and auditory pathways more commonly associated with early sensory processing. We conclude that under natural listening conditions, multisensory enhancement not only involves sites of multisensory integration but many regions of the wider semantic network and includes regions associated with extralinguistic sensory, perceptual and cognitive processing.

Re-entrant feedback processing is a key mechanism of visual object-recognition, especially under compromised viewing conditions where only sparse information is available and object features must be interpolated. Illusory Contour stimuli are commonly used in conjunction with Visual Evoked Potentials (VEP) to study these filling-in processes, with characteristic modulation of the VEP in the ∼100-150 ms timeframe associated with this re-entrant processing. Substantial inter-individual variability in timing and amplitude of feedback-related VEP modulation is observed, raising the question whether this variability might underlie inter-individual differences in the ability to form strong perceptual gestalts. Backward masking paradig ms have been used to study inter-individual variance in the ability to form robust object perceptions before processing of the mask interferes with object-recognition. Some individuals recognize objects when the time between target object and mask is extremely short, whereas others struggle to do so even at longer target-to-mask intervals. We asked whether timing and amplitude of feedback-related VEP modulations were associated with individual differences in resistance to backward masking. Participants (N=40) showed substantial performance variability in detecting Illusory Contours at intermediate target-to-mask intervals (67 ms and 117 ms), allowing us to use kmeans clustering to divide the population into four performance groups (poor, low-average, high-average, superior). There was a clear relationship between the amplitude (but not the timing) of feedback-related VEP modulation and Illusory Contour detection during backward masking. We conclude that individual differences in the strength of feedback processing in neurotypical humans lead to differences in the ability to quickly establish perceptual awareness of incomplete visual objects.

Abstract Background Autism spectrum disorders (ASD) are associated with altered sensory processing and perception. Scalp recordings of electrical brain activity time-locked to sensory events (event-related potentials; ERPs) provide precise information on the time-course of related altered neural activity, and can be used to model the cortical loci of the underlying neural networks. Establishing the test-retest reliability of these sensory brain responses in ASD is critical to their use as biomarkers of neural dysfunction in this population. Methods EEG and behavioral data were acquired from 33 children diagnosed with ASD aged 6–9.4 years old, while they performed a child-friendly task at two different time-points, separated by an average of 5.2 months. In two blocked conditions, participants responded to the occurrence of an auditory target that was either preceded or not by repeating visual stimuli. Intraclass correlation coefficients (ICCs) were used to assess test-retest reliability of measures of sensory (auditory and visual) ERPs and performance, for the two experimental conditions. To assess the degree of reliability of the variability of responses within individuals, this analysis was performed on the variance of the measurements, in addition to their means. This yielded a total of 24 measures for which ICCs were calculated. Results The data yielded significant good ICC values for 10 of the 24 measurements. These spanned across behavioral and ERPs data, experimental conditions, and mean as well as variance measures. Measures of the visual evoked responses accounted for a disproportionately large number of the significant ICCs; follow-up analyses suggested that the contribution of a greater number of trials to the visual compared to the auditory ERP partially accounted for this. Conclusions This analysis reveals that sensory ERPs and related behavior can be highly reliable across multiple measurement time-points in ASD. The data further suggest that the inter-trial and inter-participant variability reported in the ASD literature likely represents replicable individual participant neural processing differences. The stability of these neuronal readouts supports their use as biomarkers in clinical and translational studies on ASD. Given the minimum interval between test/retest sessions across our cohort, we also conclude that for the tested age-range of ~ 6 to 9.4 years, these reliability measures are valid for at least a 3-month interval. Limitations related to EEG task demands and study length in the context of a clinical trial are considered.

Abstract Background 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 in adulthood. We previously demonstrated intact auditory sensory processing, accompanied by mild sensory memory difficulties, in children and adolescents with cystinosis. Methods We investigated whether further progressive decrements in these processes would be observed in adults with cystinosis, comparing high-density auditory-evoked potential (AEP) recordings from adults with cystinosis (N = 15; ages: 19–38 years) to those of age-matched controls (N = 17). We employed a duration oddball paradigm with different stimulation rates, in which participants passively listened to regularly occurring standard tones interspersed with infrequently occurring deviant tones. Analyses focused on AEP components reflecting auditory sensory-perceptual processing (N1 and P2), sensory memory (mismatch negativity, MMN), and attentional orienting (P3a). Results Overall, adults with cystinosis produced highly similar sensory-perceptual AEP responses to those observed in controls suggesting intact early auditory cortical processing. However, significantly increased P2 and P3a amplitudes and reduced MMN at slower stimulation rates were observed, suggesting mild-to-moderate changes in auditory sensory memory and attentional processing. While cognitive testing revealed lower scores on verbal IQ and perceptual reasoning in cystinosis, these did not correlate with the AEP measures. Conclusions These neurophysiological data point to the emergence of subtle auditory processing deficits in early adulthood in cystinosis, warranting further investigation of memory and attentional processes in this population, and of their consequences for perceptual and cognitive function.

Cognitive neuroscience, in particular research on speech and language, has seen an increase in the use of linear modeling techniques for studying the processing of natural, environmental stimuli. The availability of such computational tools has prompted similar investigations in many clinical domains, facilitating the study of cognitive and sensory deficits under more naturalistic conditions. However, studying clinical (and often highly heterogeneous) cohorts introduces an added layer of complexity to such modeling procedures, potentially leading to instability of such techniques and, as a result, inconsistent findings. Here, we outline some key methodological considerations for applied research, referring to a hypothetical clinical experiment involving speech processing and worked examples of simulated electrophysiological (EEG) data. In particular, we focus on experimental design, data preprocessing, stimulus feature extraction, model design, model training and evaluation, and interpretation of model weights. Throughout the paper, we demonstrate the implementation of each step in MATLAB using the mTRF-Toolbox and discuss how to address issues that could arise in applied research. In doing so, we hope to provide better intuition on these more technical points and provide a resource for applied and clinical researchers investigating sensory and cognitive processing using ecologically rich stimuli.

Understanding of the genetic factors and molecular mechanisms underlying neurodevelopmental disorders remains incomplete. In this study, authors show that microdeletions in the gene ANKS1B lead to loss of the neuronal synapse-enriched protein AIDA-1 and to a novel neurodevelopmental syndrome

Background: There exists a cohort of children and adults who exhibit an inordinately high degree of discomfort when experiencing what would be considered moderate and manageable levels of sensory input. That is, they show over-responsivity in the face of entirely typical sound, light, touch, taste, or smell inputs, and this occurs to such an extent that it interferes with their daily functioning and reaches clinical levels of dysfunction. What marks these individuals apart is that this sensory processing disorder (SPD) is observed in the absence of other symptom clusters that would result in a diagnosis of Autism, ADHD, or other neurodevelopmental disorders more typically associated with sensory processing difficulties. One major theory forwarded to account for these SPDs posits a deficit in multisensory integration, such that the various sensory inputs are not appropriately integrated into the central nervous system, leading to an overwhelming sensory-perceptual environment, and in turn to the sensory-defensive phenotype observed in these individuals.Methods: We tested whether children (6–16 years) with an over-responsive SPD phenotype (N = 12) integrated multisensory speech differently from age-matched typically-developing controls (TD: N = 12). Participants identified monosyllabic words while background noise level and sensory modality (auditory-alone, visual-alone, audiovisual) were varied in pseudorandom order. Improved word identification when speech was both seen and heard compared to when it was simply heard served to index multisensory speech integration.Results: School-aged children with an SPD show a deficit in the ability to benefit from the combination of both seen and heard speech inputs under noisy environmental conditions, suggesting that these children do not benefit from multisensory integrative processing to the same extent as their typically developing peers. In contrast, auditory-alone performance did not differ between the groups, signifying that this multisensory deficit is not simply due to impaired processing of auditory speech.Conclusions: Children with an over-responsive SPD show a substantial reduction in their ability to benefit from complementary audiovisual speech, to enhance speech perception in a noisy environment. This has clear implications for performance in the classroom and other learning environments. Impaired multisensory integration may contribute to sensory over-reactivity that is the definitional of SPD.

BackgroundMaladaptive reactivity to sensory inputs is commonly observed in neurodevelopmental disorders (e.g., autism, ADHD). Little is known, however, about the underlying neural mechanisms. For some children, atypical sensory reactivity is the primary complaint, despite absence of another identifiable neurodevelopmental diagnosis. Studying Sensory Processing Disorder (SPD) may well provide a window into the neuropathology of these symptoms. It has been proposed that a deficit in sensory integration underlies the SPD phenotype, but objective quantification of sensory integration is lacking. Here we used neural and behavioral measures of multisensory integration (MSI), which would be affected by impaired sensory integration and for which there are well accepted objective measures, to test whether failure to integrate across the senses is associated with atypical sensory reactivity in SPD. An autism group served to determine if observed differences were unique to SPD.MethodsWe tested whether children aged 6–16 years with SPD (N = 14) integrate multisensory inputs differently from age-matched typically developing controls (TD: N = 54), or from children with an autism spectrum disorder (ASD: N = 44). Participants performed a simple reaction-time task to the occurrence of auditory, visual, and audiovisual stimuli presented in random order, while high-density recordings of electrical brain activity were made.ResultsChildren with SPD showed large reductions in the extent to which they benefited from multisensory inputs compared to TDs. The ASD group showed similarly reduced response speeding to multisensory relative to unisensory inputs. Neural evidence for MSI was seen across all three groups, with the multisensory response differing from the sum of the unisensory responses. Post hoc tests suggested the possibility of enhanced MSI in SPD in timeframes consistent with cortical sensory registration (∼60 ms), followed by reduced MSI during a timeframe consistent with object formation (∼130 ms). The ASD group also showed reduced MSI in the later timeframe.ConclusionChildren with SPD showed reduction in their ability to benefit from redundant audio-visual inputs, similar to children with ASD. Neurophysiological recordings, on the other hand, showed that major indices of MSI were largely intact, although post hoc testing pointed to periods of potential differential processing. While these exploratory electrophysiological observations point to potential sensory-perceptual differences in multisensory processing in SPD, it remains equally plausible at this stage that later attentional processing differences may yet prove responsible for the multisensory behavioral deficits uncovered here.

Cystinosis, a genetic rare disease characterized by cystine accumulation and crystallization, results in significant damage in a multitude of tissues and organs, such as the kidney, thyroid, eye, and brain. While Cystinosis’ impact on brain function is relatively mild compared to its effects on other organs, the increased lifespan of this population and thus potential for productive societal contributions have led to increased interest on the effects on brain function. Nevertheless, and despite some evidence of structural brain differences, the neural impact of the mutation is still not well characterized. Here, using a passive duration oddball paradigm (with different stimulus onset asynchronies (SOAs), representing different levels of demand on memory) and high-density electrophysiology, we tested basic auditory processing in a group of 22 children and adolescents diagnosed with Cystinosis (age range: 6-17 years old) and in neurotypical age-matched controls (N = 24). We examined whether the N1 and mismatch negativity (MMN) significantly differed between the groups and if those neural measures correlated with verbal and non-verbal IQ. Individuals diagnosed with Cystinosis presented similar N1 responses to their age-matched peers, indicating typical basic auditory processing in this population. However, whereas both groups showed similar MMN responses for the shortest (450 ms) SOA, suggesting intact change detection and sensory memory, individuals diagnosed with Cystinosis presented clearly reduced responses for the longer (900 ms and 1800 ms) SOAs. This could indicate reduced duration auditory sensory memory traces, and thus sensory memory impairment, in children and adolescents diagnosed with Cystinosis. Future work addressing other aspects of sensory and working memory is needed to understand the underlying bases of the differences described here, and their implication for higher order processing. Keywords: EEG, Auditory Evoked potential, Copy Number Variation, Event-related potential, Mismatch Negativity, Lysosomal Storage Disorder

22q11.2 deletion syndrome (also known as DiGeorge syndrome or velo-cardio-facial syndrome) is characterized by increased vulnerability to neuropsychiatric symptoms, with approximately 30% of individuals with the deletion going on to develop schizophrenia. Clinically, deficits in executive function have been noted in this population, but the underlying neural processes are not well understood. Using 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 (a critical component of executive function) in individuals with 22q11.2DS with and without psychotic symptoms, when compared to individuals with idiopathic schizophrenia and age-matched neurotypical controls. Twenty-eight participants diagnosed with 22q11.2DS (14–35 years old; 14 with at least one psychotic symptom), 15 individuals diagnosed with schizophrenia (18–63 years old) and two neurotypical control groups (one age-matched to the 22q11.2DS sample, the other age-matched to the schizophrenia sample) participated in this study. Analyses focused on the N2 and P3 no-go responses and error-related negativity (Ne) and positivity (Pe). Atypical inhibitory processing was shown behaviorally and by significantly reduced P3, Ne, and Pe responses in 22q11.2DS and schizophrenia. Interestingly, whereas P3 was only reduced in the presence of psychotic symptoms, Ne and Pe were equally reduced in schizophrenia and 22q11.2DS, regardless of the presence of symptoms. We argue that while P3 may be a marker of disease severity, Ne and Pe might be candidate markers of risk.

Abstract Background Estimates of the prevalence of developmental dyslexia in the general population range from 5% to as many as 10%. Symptoms include reading, writing, and language deficits, but the severity and mix of symptoms can vary widely across individuals. In at least some people with dyslexia, the structure and function of the cerebellum may be disordered. Saccadic adaptation requires proper function of the cerebellum and brainstem circuitry and might provide a simple, noninvasive assay for early identification and sub-phenotyping in populations of children who may have dyslexia. Methods Children between the ages of 7 and 15 served as participants in this experiment. Fifteen had been diagnosed with developmental dyslexia and an additional 15 were typically developing children. Five of the participants diagnosed with dyslexia were also diagnosed with an attention deficit hyperactivity disroder and were excluded from further analyses. Participants performed in a saccadic adaptation task in which visual errors were introduced at the end of saccadic eye movements. The amplitudes of primary saccades were measured and plotted as a function of the order in which they occurred. Lines of best fit were calculated. Significant changes in the amplitude of primary saccades were identified. Results 12/15 typically developing children had significant adaptation of saccade amplitude in this experiment. 1/10 participants with dyslexia appropriately altered saccade amplitudes to reduce the visual error introduced in the saccade adaptation paradigm. Conclusions Proper cerebellar function is required for saccadic adaptation, but in at least some children with dyslexia, cerebellar structure and function may be disordered. Consistent with this hypothesis, the data presented in this report clearly illustrate a difference in the ability of children with dyslexia to adapt saccade amplitudes in response to imposed visual errors. Saccadic adaptation might provide a noninvasive assay for early identification of dyslexia. Future work will determine whether reduced saccadic adaptation is pervasive in dyslexia or whether this identifies a sub-phenotype within the larger population of people identified with reading and language deficits.

Failure to appropriately develop multisensory integration (MSI) of audiovisual speech may affect a child's ability to attain optimal communication. Studies have shown protracted development of MSI into late-childhood and identified deficits in MSI in children with an autism spectrum disorder (ASD). Currently, the neural basis of acquisition of this ability is not well understood. Here, we developed a computational model informed by neurophysiology to analyze possible mechanisms underlying MSI maturation, and its delayed development in ASD. The model posits that strengthening of feedforward and cross-sensory connections, responsible for the alignment of auditory and visual speech sound representations in posterior superior temporal gyrus/sulcus, can explain behavioral data on the acquisition of MSI. This was simulated by a training phase during which the network was exposed to unisensory and multisensory stimuli, and projections were crafted by Hebbian rules of potentiation and depression. In its mature architecture, the network also reproduced the well-known multisensory McGurk speech effect. Deficits in audiovisual speech perception in ASD were well accounted for by fewer multisensory exposures, compatible with a lack of attention, but not by reduced synaptic connectivity or synaptic plasticity.

Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

The notion of the temporal window of integration, when applied in a multisensory context, refers to the breadth of the interval across which the brain perceives two stimuli from different sensory modalities as synchronous. It maintains a unitary perception of multisensory events despite physical and biophysical timing differences between the senses. The boundaries of the window can be influenced by attention and past sensory experience. Here we examined whether task demands could also influence the multisensory temporal window of integration. We varied the stimulus onset asynchrony between simple, short-lasting auditory and visual stimuli while participants performed two tasks in separate blocks: a temporal order judgment task that required the discrimination of subtle auditory-visual asynchronies, and a reaction time task to the first incoming stimulus irrespective of its sensory modality. We defined the temporal window of integration as the range of stimulus onset asynchronies where performance was below 75% in the temporal order judgment task, as well as the range of stimulus onset asynchronies where responses showed multisensory facilitation (race model violation) in the reaction time task. In 5 of 11 participants, we observed audio-visual stimulus onset asynchronies where reaction time was significantly accelerated (indicating successful integration in this task) while performance was accurate in the temporal order judgment task (indicating successful segregation in that task). This dissociation suggests that in some participants, the boundaries of the temporal window of integration can adaptively recalibrate in order to optimize performance according to specific task demands.

That language processing is primarily a function of the left hemisphere has led to the supposition that auditory temporal discrimination is particularly well-tuned in the left hemisphere, since speech discrimination is thought to rely heavily on the registration of temporal transitions. However, physiological data have not consistently supported this view. Rather, functional imaging studies often show equally strong, if not stronger, contributions from the right hemisphere during temporal processing tasks, suggesting a more complex underlying neural substrate. The mismatch negativity (MMN) component of the human auditory evoked-potential (AEP) provides a sensitive metric of duration processing in human auditory cortex and lateralization of MMN can be readily assayed when sufficiently dense electrode arrays are employed. Here, the sensitivity of the left and right auditory cortex for temporal processing was measured by recording the MMN to small duration deviants presented to either the left or right ear. We found that duration deviants differing by just 15% (i.e. rare 115 ms tones presented in a stream of 100 ms tones) elicited a significant MMN for tones presented to the left ear (biasing the right hemisphere). However, deviants presented to the right ear elicited no detectable MMN for this separation. Further, participants detected significantly more duration deviants and committed fewer false alarms for tones presented to the left ear during a subsequent psychophysical testing session. In contrast to the prevalent model, these results point to equivalent if not greater right hemisphere contributions to temporal processing of small duration changes.