22q11.2 Deletion Syndrome (22q11.2DS) is the strongest known molecular risk factor for schizophrenia. Brain responses to auditory stimuli have been studied extensively in schizophrenia and described as potential biomarkers of vulnerability to psychosis. We sought to understand whether these responses might aid in differentiating individuals with 22q11.2DS as a function of psychotic symptoms, and ultimately serve as signals of risk for schizophrenia. A duration oddball paradigm and high-density electrophysiology were used to test auditory processing in 26 individuals with 22q11.2DS (13-35 years old, 17 females) with varying degrees of psychotic symptomatology and in 26 age- and sex-matched neurotypical controls (NT). Presentation rate varied across three levels, to examine the effect of increasing demands on memory and the integrity of sensory adaptation. We tested whether N1 and mismatch negativity (MMN), typically reduced in schizophrenia, related to clinical/cognitive measures, and how they were affected by presentation rate. N1 adaptation effects interacted with psychotic symptomatology: Compared to an NT group, individuals with 22q11.2DS but no psychotic symptomatology presented larger adaptation effects, whereas those with psychotic symptomatology presented smaller effects. In contrast, individuals with 22q11.2DS showed increased effects of presentation rate on MMN amplitude, regardless of the presence of symptoms. While IQ and working memory were lower in the 22q11.2DS group, these measures did not correlate with the electrophysiological data. These findings suggest the presence of two distinct mechanisms: One intrinsic to 22q11.2DS resulting in increased N1 and MMN responses; another related to psychosis leading to a decreased N1 response.

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.

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.

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.

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.

Visual sensory processing deficits are consistently observed in schizophrenia, with clear amplitude reduction of the visual evoked potential (VEP) during the initial 50-150 ms of processing. Similar deficits are seen in unaffected first-degree relatives and drug-naïve first-episode patients, pointing to these deficits as potential endophenotypic markers. Schizophrenia is also associated with deficits in neural plasticity, implicating dysfunction of both glutamatergic and GABAergic systems. Here, we sought to understand the intersection of these two domains, asking whether short-term plasticity during early visual processing is specifically affected in schizophrenia.

Stimulant drug use in HIV + patients is associated with poor personal and public health outcomes, including high-risk sexual behavior and faster progression from HIV to AIDS. Inhibitory control--the ability to withhold a thought, feeling, or action--is a central construct involved in the minimization of risk-taking behaviors. Recent neuroimaging and behavioral evidence indicate normalization of inhibitory control processes in former cocaine users as a function of the duration of drug abstinence, but it is unknown whether this recovery trajectory persists in former users with comorbid HIV. Here, we investigate the neural correlates of inhibitory control in 103 human subjects using high-density EEG recording as participants performed a Go/NoGo response inhibition task. Four groups of participants were recruited, varying on HIV and cocaine-dependence status. Electrophysiological responses to successful inhibitions and behavioral task performance were compared among groups. Results indicate persistent behavioral and neurophysiological impairment in HIV+ patients' response inhibition despite current abstinence from cocaine. Analysis of task performance showed that HIV+ abstinent cocaine-dependent participants demonstrate the lowest performance of all groups across all metrics of task accuracy. Planned comparisons of electrophysiological components revealed a main effect of scalp site and an interaction between HIV-status and scalp site on N2 amplitudes during successful inhibitions. Analysis of the P3 time region showed a main effect of scalp site and an interaction between HIV-status and cocaine dependence. These results suggest synergistic alterations in the neurophysiology of response inhibition and indicate that abstinence-related recovery of inhibitory control may be attenuated in patients with HIV.

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.

Individuals on the autism spectrum often exhibit atypicality in their sensory perception, but the neural underpinnings of these perceptual differences remain incompletely understood. One proposed mechanism is an imbalance in higher-order feedback re-entrant inputs to early sensory cortices during sensory perception, leading to increased propensity to focus on local object features over global context. We explored this theory by measuring visual evoked potentials during contour integration as considerable work has revealed that these processes are largely driven by feedback inputs from higher-order ventral visual stream regions. We tested the hypothesis that autistic individuals would have attenuated evoked responses to illusory contours compared with neurotypical controls. Electrophysiology was acquired while 29 autistic and 31 neurotypical children (7-17 years old, inclusive of both males and females) passively viewed a random series of Kanizsa figure stimuli, each consisting of four inducers that were aligned either at random rotational angles or such that contour integration would form an illusory square. Autistic children demonstrated attenuated automatic contour integration over lateral occipital regions relative to neurotypical controls. The data are discussed in terms of the role of predictive feedback processes on perception of global stimulus features and the notion that weakened "priors" may play a role in the visual processing anomalies seen in autism.SIGNIFICANCE STATEMENT Children on the autism spectrum differ from typically developing children in many aspects of their processing of sensory stimuli. One proposed mechanism for these differences is an imbalance in higher-order feedback to primary sensory regions, leading to an increased focus on local object features rather than global context. However, systematic investigation of these feedback mechanisms remains limited. Using EEG and a visual illusion paradigm that is highly dependent on intact feedback processing, we demonstrated significant disruptions to visual feedback processing in children with autism. This provides much needed experimental evidence that advances our understanding of the contribution of feedback processing to visual perception in autism spectrum disorder.

Rett syndrome (RTT), a rare neurodevelopmental disorder caused by mutations in the MECP2 gene, is typified by profound cognitive impairment and severe language impairment, rendering it very difficult to accurately measure auditory processing capabilities behaviorally in this population. Here we leverage the mismatch negativity (MMN) component of the event-related potential to measure the ability of RTT patients to decode and store occasional duration deviations in a stream of auditory stimuli. Sensory memory for duration, crucial for speech comprehension, has not been studied in RTT.High-density electroencephalography was successfully recorded in 18 females with RTT and 27 age-matched typically developing (TD) controls (aged 6-22 years). Data from seven RTT and three TD participants were excluded for excessive noise. Stimuli were 1 kHz tones with a standard duration of 100 ms and deviant duration of 180 ms. To assess the sustainability of sensory memory, stimulus presentation rate was varied with stimulus onset asynchronies (SOAs) of 450, 900, and 1800 ms. MMNs with maximum negativity over fronto-central scalp and a latency of 220-230 ms were clearly evident for each presentation rate in the TD group, but only for the shortest SOA in the RTT group. Repeated-measures ANOVA revealed a significant group by SOA interaction. MMN amplitude correlated with age in the TD group only. MMN amplitude was not correlated with the Rett Syndrome Severity Scale. This study indicates that while RTT patients can decode deviations in auditory duration, the span of this sensory memory system is severely foreshortened, with likely implications for speech decoding abilities.

Cocaine use is associated with the transmission of human immunodeficiency (HIV) virus through risky sexual behavior. In HIV+ individuals, cocaine use is linked with poor health outcomes, including HIV-medication non-adherence and faster disease progression. Both HIV and cocaine dependence are associated with reduced integrity of cerebral white matter (WM), but the effects of HIV during cocaine abstinence have not yet been explored. We used diffusion tensor imaging (DTI) to understand the effect of combined HIV+ serostatus and former cocaine dependence on cerebral WM integrity. DTI data obtained from 15 HIV+ women with a history of cocaine dependence (COC+/HIV+) and 21 healthy females were included in the analysis. Diffusion-based measures [fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity, and axial diffusivity] were examined using tract-based spatial statistics and region-of-interest analyses. In a whole-brain analysis, COC+/HIV+ women showed significantly reduced FA and increased RD in all major WM tracts, except the left corticospinal tract for RD. The tract with greatest percentage of voxels showing significant between-group differences was the forceps minor (FA: 75.6%, RD: 59.7%). These widespread changes in diffusion measures indicate an extensive neuropathological effect of HIV and former cocaine dependence on WM.

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.

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.

The processing of sensory information and the generation of motor commands needed to produce coordinated actions can interfere with ongoing cognitive tasks. Even simple motor behaviors like walking can alter cognitive task performance. This cognitive-motor interference (CMI) could arise from disruption of planning in anticipation of carrying out the task (proactive control) and/or from disruption of the execution of the task (reactive control). In young healthy adults, walking-induced interference with behavioral performance may not be readily observable because flexibility in neural circuits can compensate for the added demands of simultaneous loads. In this study, cognitive-motor loads were systematically increased during cued task-switching while underlying neurophysiologic changes in proactive and reactive mechanisms were measured. Brain activity was recorded from 22 healthy young adults using 64-channel electroencephalography (EEG) based Mobile Brain/Body Imaging (MoBI) as they alternately sat or walked during performance of cued task-switching. Walking altered neurophysiological indices of both proactive and reactive control. Walking amplified cue-evoked late fontal slow waves, and reduced the amplitude of target-evoked fronto-central N2 and parietal P3. The effects of walking on evoked neural responses systematically increased as the task became increasingly difficult. This may provide an objective brain marker of increasing cognitive load, and may prove to be useful in identifying seemingly healthy individuals who are currently able to disguise ongoing degenerative processes through active compensation. If, however, degeneration continues unabated these people may reach a compensatory limit at which point both cognitive performance and control of coordinated actions may decline rapidly.

During mobile brain/body imaging (MoBI) experiments, electroencephalography and motion capture systems are used in concert to record high temporal resolution neural activity and movement kinematics while participants perform demanding perceptual and cognitive tasks in a naturalistic environment. A typical MoBI setup involves positioning multi-channel electrode caps based on anatomical fiducials as well as experimenter and participant intuition regarding the scalp midpoint location (i.e., Cz). Researchers often use the "template" electrode locations provided by the manufacturer, however, the "actual" electrode locations can vary based on each participant's head morphology. Accounting for differences in head morphologies could provide more accurate clinical diagnostic information when using MoBI to identify neurological deficits in patients with motor, sensory, or cognitive impairments. Here, we asked whether the existing motion capture system used in a MoBI setup could be easily adapted to improve spatial localization of electrodes across participants without requiring additional or specialized equipment that might impede clinical adoption. Using standard electrode configurations, infrared markers were placed on a subset of electrodes and anatomical fiducials, and the remaining electrode locations were estimated using spherical or ellipsoid models. We identified differences in event-related potentials between "template" and "actual" electrode locations during a Go/No-Go task (p < 9.8e-5) and an object-manipulation task (p < 9.8e-5). Thus, the motion capture system already used in MoBI experiments can be effectively deployed to accurately register and quantify the neural activity. Improving the spatial localization without needing specialized hardware or additional setup time to the workflow has important real-world implications for translating MoBI to clinical environments.

Caffeine, a very widely used and potent neuromodulator, easily crosses the placental barrier, but relatively little is known about the long-term impact of gestational caffeine exposure (GCE) on neurodevelopment. Here, we leverage magnetic resonance imaging (MRI) data, collected from a very large sample of 9157 children, aged 9-10 years, as part of the Adolescent Brain and Cognitive Developmentsm (ABCD ®) study, to investigate brain structural outcomes at 27 major fiber tracts as a function of GCE. Significant relationships between GCE and fractional anisotropy (FA) measures in the inferior fronto-occipito fasciculus and corticospinal tract of the left hemisphere (IFOF-LH; CST-LH) were detected via mixed effects binomial regression. We further investigated the interaction between these fiber tracts, GCE, cognitive measures (working memory, task efficiency), and psychopathology measures (externalization, internalization, somatization, and neurodevelopment). GCE was associated with poorer outcomes on all measures of psychopathology but had negligible effect on cognitive measures. Higher FA values in both fiber tracts were associated with decreased neurodevelopmental problems and improved performance on both cognitive tasks. We also identified a decreased association between FA in the CST-LH and task efficiency in the GCE group. These findings suggest that GCE can lead to future neurodevelopmental complications and that this occurs, in part, through alteration of the microstructure of critical fiber tracts such as the IFOF-LH and CST-LH. These data suggest that current guidelines regarding limiting caffeine intake during pregnancy may require some recalibration.

Individuals with a diagnosis of co-morbid HIV infection and cocaine use disorder are at higher risk of poor health outcomes. Active cocaine users, both with and without HIV infection, show clear deficits in response inhibition and other measures of executive function that are instrumental in maintaining drug abstinence, factors that may complicate treatment. Neuroimaging and behavioral evidence indicate normalization of executive control processes in former cocaine users as a function of the duration of drug abstinence, but it is unknown to what extent co-morbid diagnosis of HIV affects this process. To this end, we investigate the combinatorial effects of HIV and cocaine dependence on the neural substrates of cognitive control in cocaine-abstinent individuals with a history of cocaine dependence. Blood-oxygen level dependent signal changes were measured as 86 participants performed a Go/NoGo response inhibition task while undergoing functional magnetic resonance imaging (fMRI). Four groups of participants were selected based on HIV and cocaine-dependence status. Participants affected by both conditions demonstrated the lowest response accuracy of all participant groups. In a region of interest analysis, hyperactivation in the left putamen and midline-cingulate hyperactivation was observed in individuals with both HIV and cocaine dependence relative to individuals with only one condition. Results of a whole-brain analysis indicate response inhibition-related hyperactivation in the bilateral supplementary motor area, bilateral hippocampi, bilateral primary somatosensory areas, right dorsal anterior cingulate, and left insula in the CD+/HIV+ group relative to all other groups. These results indicate complex and interactive alterations in neural activation during response inhibition and highlight the importance of examining the neurocognitive effects of co-morbid conditions.

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.

Age-related reductions in cognitive flexibility may limit modulation of control processes during systematic increases to cognitive-motor demands, exacerbating dual-task costs. In this study, behavioral and neurophysiologic changes to proactive and reactive control during progressive cognitive-motor demands were compared across older and younger adults to explore the basis for age-differences in cognitive-motor interference (CMI). 19 younger (19 - 29 years old, mean age = 22.84 +/- 2.75 years, 6 male, 13 female) and 18 older (60 - 77 years old, mean age = 67.89 +/- 4.60 years, 9 male, 9 female) healthy adults completed cued task-switching while alternating between sitting and walking on a treadmill. Gait kinematics, task performance measures, and brain activity were recorded using electroencephalography (EEG) based Mobile Brain/Body Imaging (MoBI). Response accuracy on easier trial types improved in younger, but not older adults when they walked while performing the cognitive task. As difficulty increased, walking provoked accuracy costs in older, but not younger adults. Both groups registered faster responses and reduced gait variability during dual-task walking. Older adults exhibited lower amplitude modulations of proactive and reactive neural activity as cognitive-motor demands systematically increased, which may reflect reduced flexibility for progressive preparatory and reactive adjustments over behavioral control.

In young adults, pairing a cognitive task with walking can have different effects on gait and cognitive task performance. In some cases, performance clearly declines whereas in others compensatory mechanisms maintain performance. This study investigates the preliminary finding of behavioral improvement in Go/NoGo response inhibition task performance during walking compared with sitting, which was observed at the piloting stage.