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Objective Port-wine birthmark (PWB) is a common occurrence in the newborn, and general pediatricians, dermatologists, and ophthalmologists are often called on to make an assessment of risk for Sturge-Weber syndrome (SWS) due to workforce shortages in pediatric neurologists and MRI’s low sensitivity for SWS brain involvement in infants. We therefore aimed to develop a quantitative EEG (qEEG) approach to safely screen young infants with PWB for SWS risk and optimal timing of diagnostic MRI. Methods Forty-eight infants (prior to first birthday) underwent EEG recording. Signal processing methods compared voltage between left and right sides using a previously defined pipeline and diagnostic threshold. In this test sample, we compared sensitivity/specificity of the qEEG metric against MRI performed after the first birthday. We also used likelihood ratio testing to determine whether qEEG adds incremental information beyond topographical extent of PWB, another risk marker of brain involvement. Results qEEG helped predict SWS risk in the first year of life (p = 0.031), with a sensitivity of 50% and a specificity of 81%. It added about 40% incremental information beyond PWB extent alone (p = 0.042). Conclusion qEEG adds information to risk prediction in infants with facial PWB. Significance qEEG can be used to help determine whether to obtain an MRI in the first year of life. The data collected can assist in developing a predictive model risk calculator that incorporates both PWB extent and qEEG results, which can be validated and then employed in the community.

SUMMARY The field of clinical EEG has had an uneasy relationship with the use of this technology for clinical cognitive applications and often for good reason. However, apart from its clinical use, EEG has had a tradition as a major tool in cognitive psychology and cognitive neuroscience dating back at least to the 1960s. Based on accumulated knowledge from its research application, EEG-based biomarkers are beginning to see applications in clinical trials and may eventually enter clinical care. We address concerns surrounding quality control, the treatment of artifact, and normal variants and how developments in engineering, biomarker validation, and implementation science rigorously applied to these tools can lead to well-justified approaches.

Background Sturge-Weber syndrome is a rare neurovascular disorder associated with capillary malformation, seizures, cognitive impairments, and stroke-like episodes (SLEs), arising from a somatic activating mutation in GNAQ. Studies suggest this mutation may cause hyperactivation of the mammalian target of rapamycin pathway. Sirolimus is an mammalian target of rapamycin inhibitor studied in other vascular anomalies and a potentially promising therapy in Sturge-Weber syndrome. Methods Ten patients with Sturge-Weber syndrome brain involvement and cognitive impairments were enrolled. Oral sirolimus was taken for six months (maximum dose: 2 mg/day, target trough level: 4-6 ng/mL). Neuropsychological testing, electroencephalography, and port-wine score were performed at baseline and after six months on sirolimus. Neuroquality of life, adverse events, and Sturge-Weber Syndrome Neurological Score (neuroscore) were recorded at each visit. Results Sirolimus was generally well tolerated; one subject withdrew early. Adverse events considered related to sirolimus were mostly (15/16) grade 1. A significant increase in processing speed was seen in the overall group (P = 0.031); five of nine patients with available data demonstrated statistically rare improvement in processing speed. Improvements were seen in the neuroquality of life subscales measuring anger (P = 0.011), cognitive function (P = 0.015), and depression (P = 0.046). Three subjects experiencing SLEs before and during the study reported shortened recovery times while on sirolimus. Conclusions Sirolimus was well tolerated in individuals with Sturge-Weber syndrome and may be beneficial for cognitive impairments, especially in patients with impaired processing speed or a history of SLE. A future, randomized, placebo-controlled trial of sirolimus in patients with Sturge-Weber syndrome is needed to further understand these potentially beneficial effects.

Children with autism spectrum disorder (ASD) have difficulties perceiving and producing skilled gestures, or praxis. The inferior parietal lobule (IPL) is crucial to praxis acquisition and expression, yet how IPL connectivity contributes to autism-associated impairments in praxis as well as social-communicative skill remains unclear. Using resting-state functional magnetic resonance imaging, we applied independent component analysis to test how IPL connectivity relates to praxis and social-communicative skills in children with and without ASD. Across all children (with/without ASD), praxis positively correlated with connectivity of left posterior-IPL with the left dorsal premotor cortex and with the bilateral posterior/medial parietal cortex. Praxis also correlated with connectivity of right central-IPL connectivity with the left intraparietal sulcus and medial parietal lobe. Further, in children with ASD, poorer praxis and social-communicative skills both correlated with weaker right central-IPL connectivity with the left cerebellum, posterior cingulate, and right dorsal premotor cortex. Our findings suggest that IPL connectivity is linked to praxis development, that contributions arise bilaterally, and that right IPL connectivity is associated with impaired praxis and social-communicative skills in autism. The findings underscore the potential impact of IPL connectivity and impaired skill acquisition on the development of a range of social-communicative and motor functions during childhood, including autism-associated impairments.

In this study, we propose a two-stage procedure for hypothesis testing, where the first stage is conventional hypothesis testing and the second is an equivalence testing procedure using an introduced Empirical Equivalence Bound. In 2016, the American Statistical Association released a policy statement on P-values to clarify the proper use and interpretation in response to the criticism of reproducibility and replicability in scientific findings. A recent solution to improve reproducibility and transparency in statistical hypothesis testing is to integrate P-values (or confidence intervals) with practical or scientific significance. Similar ideas have been proposed via the equivalence test, where the goal is to infer equality under a presumption (null) of inequality of parameters. However, in these testing procedures, the definition of scientific significance/equivalence can be subjective. To circumvent this drawback, we introduce a B-value and the Empirical Equivalence Bound, which are both estimated from the data. Performing a second-stage equivalence test, our procedure offers an opportunity to correct for false positive discoveries and improve the reproducibility in findings across studies.

Multisensory objects that are frequently encountered in the natural environment lead to strong associations across a distributed sensory cortical network, with the end result experience of a unitary percept. Remarkably little is known, however, about the cortical processes sub-serving multisensory object formation and recognition. To advance our understanding in this important domain, the present study investigated the brain processes involved in learning and identification of novel visual-auditory objects. Specifically, we introduce and test a rudimentary three-stage model of multisensory object-formation and processing. Thirty adults were remotely trained for a week to recognize a novel class of multisensory objects (3D shapes paired to complex sounds), and high-density event related potentials (ERPs) were recorded to the corresponding unisensory (shapes or sounds only) and multisensory (shapes and sounds) stimuli, before and after intensive training. We identified three major stages of multisensory processing: 1) an early, multisensory, automatic effect (250 ms) that appears to be involved in both object recognition and possibly memory consolidation. Results from this study provide support for multiple stages of multisensory object learning and recognition that are subserved by an extended network of cortical areas.

Children with ADHD show developmentally abnormal levels of mirror overflow-unintentional movements occurring symmetrically opposite of intentional movements. Because mirror overflow correlates with ADHD behavioral symptoms, the study of disinhibition in motor control may shed light on physiologic mechanisms underlying impaired behavioral/cognitive control. This is a case-controlled study of EEG recording from 25 children with ADHD and 25 typically developing (TD) controls performing unilateral sequential finger tapping, with overflow movements measured using electronic goniometers. Consistent with previously published findings, children with ADHD showed increased mirror overflow as compared with TD peers. EEG findings revealed less lateralized alpha modulation (event-related desynchronization; ERD) and decreased magnitude of beta ERD in ADHD; both alpha and beta ERD reflect cortical activation. Moderation analysis revealed a significant association between beta ERD and overflow, independent of diagnosis; and an equivocal (p = .08) effect of diagnosis on the relationship between alpha ERD and overflow, with a significant effect in children with ADHD but not TD children. These results suggest two mechanisms involved with mirror overflow: one reflected in beta ipsilateral to the intentional movement and relevant to both children with ADHD and controls, and the other seemingly more specific to ADHD (alpha, contralateral to movement).

Autism spectrum disorder (ASD) consists of altered performance of a range of skills, including social/communicative and motor skills. It is unclear whether this altered performance results from atypical acquisition or learning of the skills or from atypical "online" performance of the skills. Atypicalities of skilled actions that require both motor and cognitive resources, such as abnormal gesturing, are highly prevalent in ASD and are easier to study in a laboratory context than are social/communicative skills. Imitation has long been known to be impaired in ASD; because learning via imitation is a prime method by which humans acquire skills, we tested the hypothesis that children with ASD show alterations in learning novel gestures via imitation. Eighteen participants with ASD and IQ > 80, ages 8-12.9 years, and 19 typically developing peers performed a task in which they watched a video of a model performing a novel, meaningless arm/hand gesture and copied the gesture. Each gesture video/copy sequence was repeated 4-6 times. Eight gestures were analyzed. Examination of learning trajectories revealed that while children with ASD made nearly as much progress in learning from repetition 1 to repetition 4, the shape of the learning curves differed. Causal modeling demonstrated the shape of the learning curve influenced both the performance of overlearned gestures and autism severity, suggesting that it is in the index of learning mechanisms relevant both to motor skills and to autism core features. Autism Res 2020, 13: 777-784.. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Imitation is a route by which humans learn a wide range of skills, naturally and in therapies. Imitation is known to be altered in autism spectrum disorder (ASD), but learning via imitation has not been rigorously examined. We found that the shape of the learning curve is altered in ASD, in a way that has a significant impact both on measures of autism severity and of other motor skills.

Our current diagnostic methods for treatment planning in Psychiatry and Neurodevelopmental Disabilities leave room for improvement, and null results in clinical trials in these fields may be a result of insufficient tools for patient stratification. Great hope has been placed in novel technologies to improve clinical and trial outcomes, but we have yet to see a substantial change in clinical practice. As we examine attempts at biomarker validation within these fields, we find that it may be the diagnoses themselves that fall short. We now need to improve neuropsychiatric nosologies with a focus on validity based not solely on behavioral features, but on a synthesis that includes genetic and biological data as well. The eventual goal is diagnostic biomarkers and diagnoses themselves based on distinct mechanisms, but such an understanding of the causal relationship across levels of analysis is likely to be elusive for some time. Rather, we propose an approach in the near-term that deconstructs diagnosis into a series of independent, empiric and clinically relevant associations among a single, defined patient group, a single biomarker, a single intervention and a single clinical outcome. Incremental study across patient groups, interventions, outcomes and modalities will lead to a more interdigitated network of knowledge, and correlations in metrics across levels of analysis will eventually give way to the causal understanding that will allow for mechanistically based diagnoses.

Mirror overflow is involuntary movement that accompanies unilateral voluntary movement on the opposite side of the body, and is commonly seen in Attention-Deficit/Hyperactivity Disorder (ADHD). Children with ADHD show asymmetry in mirror overflow between dominant and non-dominant hand, yet there are competing mechanistic accounts of why this occurs. Using EEG during a sequential, unimanual finger-tapping task, we found that children with ADHD exhibited significantly more mirror overflow than typically developing (TD) controls, especially during the tapping of the non-dominant hand. Furthermore, source-level EEG oscillation analysis revealed that children with ADHD showed decreased alpha (8-12 Hz) event-related desynchronization (ERD) compared with controls in both hemispheres, but only during tapping of the non-dominant hand. Moreover, only the ERD ipsilateral to the mirror overflow during non-dominant hand movement correlated with both magnitude of overflow movements and higher ADHD symptom severity (Conners ADHD Hyperactivity/Impulsiveness scale) in children with ADHD. TD controls did not show these relationships. Our findings suggest that EEG differences in finger-tapping in ADHD are related primarily to voluntary movement in the non-dominant hand. Our results are also consistent with the Ipsilateral Corticospinal Tract (CST) Hypothesis, which posits that the atypical persistence of mirror overflow in ADHD may originate in the sensorimotor areas ipsilateral to mirror overflow and be transmitted via non-decussating CST fibers.

Children with attention-deficit/hyperactivity disorder (ADHD) have previously shown a decreased magnitude of event-related desynchronization (ERD) during a finger-tapping task, with a large between-group effect. Because the neurobiology underlying several TMS measures have been studied in multiple contexts, we compared ERD and three TMS measures (Resting Motor Threshold [RMT], Short-Interval Cortical Inhibition [SICI] and Task-Related Up-Modulation [TRUM]) within 14 participants with ADHD (ages 8-12y) and 17 control children. The TD group showed a correlation between greater RMT and greater magnitude of alpha (10-13Hz, here) ERD, and there was no diagnostic interaction effect, consistent with a rudimentary model of greater needed energy input to stimulate movement. Similarly, inhibition measured by SICI was also greater in the TD group when the magnitude of movement-related ERD was higher; there was a miniscule diagnostic interaction effect. Finally, TRUM during a response-inhibition task showed an unanticipated pattern: in TD children, the greater TMS task modulation (TRUM) was associated with a smaller magnitude of ERD during finger-tapping. The ADHD group showed the opposite direction of association: greater TRUM was associated with larger-magnitude ERD. Prior EEG results have demonstrated specific alterations of task-related modulation of cortical physiology, and the current results provide a fulcrum for multimodal study.

Children with attention-deficit/hyperactivity disorder (ADHD) have previously shown a decreased magnitude of event-related desynchronization (ERD) during a finger-tapping task, with a large between-group effect. Because the neurobiology underlying several transcranial magnetic stimulation (TMS) measures have been studied in multiple contexts, we compared ERD and 3 TMS measures (resting motor threshold [RMT], short-interval cortical inhibition [SICI], and task-related up-modulation [TRUM]) within 14 participants with ADHD (ages 8–12 years) and 17 control children. The typically developing (TD) group showed a correlation between greater RMT and greater magnitude of alpha (10–13 Hz, here) ERD, and there was no diagnostic interaction effect, consistent with a rudimentary model of greater needed energy input to stimulate movement. Similarly, inhibition measured by SICI was also greater in the TD group when the magnitude of movement-related ERD was higher; there was a miniscule diagnostic interaction effect. Finally, TRUM during a response-inhibition task showed an unanticipated pattern: in TD children, the greater TMS task modulation (TRUM) was associated with a smaller magnitude of ERD during finger-tapping. The ADHD group showed the opposite direction of association: Greater TRUM was associated with larger magnitude of ERD. Prior EEG results have demonstrated specific alterations of task-related modulation of cortical physiology, and the current results provide a fulcrum for multimodal study.

Mirror overflow is involuntary movement that accompanies unilateral voluntary movement on the opposite side of the body, and is commonly seen in Attention-Deficit/Hyperactivity Disorder (ADHD). Children with ADHD show asymmetry in mirror overflow between dominant and non-dominant hand, yet there are competing mechanistic accounts of why this occurs. Using EEG during a sequential, unimanual finger-tapping task, we found that children with ADHD exhibited significantly more mirror overflow than typically developing (TD) controls, especially during the tapping of the non-dominant hand. Furthermore, source-level EEG oscillation analysis revealed that children with ADHD showed decreased alpha (8–12 Hz) event-related desynchronization (ERD) compared with controls in both hemispheres, but only during tapping of the non-dominant hand. Moreover, only the ERD ipsilateral to the mirror overflow during non-dominant hand movement correlated with both magnitude of overflow movements and higher ADHD symptom severity (Conners ADHD Hyperactivity/Impulsiveness scale) in children with ADHD. TD controls did not show these relationships. Our findings suggest that EEG differences in finger-tapping in ADHD are related primarily to voluntary movement in the non-dominant hand. Our results are also consistent with the Ipsilateral Corticospinal Tract (CST) Hypothesis, which posits that the atypical persistence of mirror overflow in ADHD may originate in the sensorimotor areas ipsilateral to mirror overflow and be transmitted via non-decussating CST fibers.

Decreasing biomedical research support over the past decade has driven many talented young scientists to seek careers outside academia. In 2011, the Department of Neurology at Johns Hopkins University School of Medicine developed an internal grant review program (IGRP) to systematically review career development awards (CDAs) and research grants (e.g., R01s) for junior investigators prior to NIH submission. With IGRP implementation, we observed significant increases in the number of CDAs and R-grants awarded to junior investigators. Thus, internal grant review is an effective means for supporting junior faculty and help them retain their research roles within academia. This article is protected by copyright. All rights reserved.

Objective:To determine safety and perform a preliminary assessment of dose-dependent efficacy of dextromethorphan in normalizing electrographic spikes, clinical seizures, and behavioral and cognitive functions in girls with Rett syndrome.Methods:We used a prospective randomized, open-label trial in fast metabolizers of dextromethorphan to examine the effect of dextromethorphan on core clinical features of Rett syndrome. Interictal spike activity and clinical seizures were determined using EEG and parent reporting. Cognitive data were obtained using the Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales, while behavioral data were obtained from parent-completed checklists, the Aberrant Behavior Checklist–Community Version, and the Screen for Social Interaction. Anthropometric data were obtained according to the National Health and Nutrition Examination Survey. The Rett Syndrome Severity Scale provided a clinical global impression of the effect of dextromethorphan on clinical severity.Results:Dextromethorphan is safe for use in 3- to 15-year-old girls with Rett syndrome. Thirty-five girls were treated with 1 of 3 doses of dextromethorphan over a period of 6 months. Statistically significant dose-dependent improvements were seen in clinical seizures, receptive language, and behavioral hyperactivity. There was no significant improvement in global clinical severity as measured by the Rett Syndrome Severity Scale.Conclusions:Dextromethorphan is a potent noncompetitive antagonist of the NMDA receptor channel that is safe for use in young girls with Rett syndrome. Preliminary evidence suggests that dextromethorphan may improve some core features of Rett syndrome.Classification of evidence:This study provides Class IV evidence that dextromethorphan at various doses does not change EEG spike counts over 6 months, though precision was limited to exclude an important effect.

Functional connectivity differences between children with autism spectrum disorder (ASD) and typically developing children have been described in multiple datasets. However, few studies examine the task-related changes in connectivity in disorder-relevant behavioral paradigms. In this paper, we examined the task-related changes in functional connectivity using EEG and a movement-based paradigm that has behavioral relevance to ASD. Resting-state studies motivated our hypothesis that children with ASD would show a decreased magnitude of functional connectivity during the performance of a motor-control task. Contrary to our initial hypothesis, however, we observed that task-related modulation of functional connectivity in children with ASD was in the direction opposite to that of TDs. The task-related connectivity changes were correlated with clinical symptom scores. Our results suggest that children with ASD may have differences in cortical segregation/integration during the performance of a task, and that part of the differences in connectivity modulation may serve as a compensatory mechanism. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Decreased connectivity between brain regions is thought to cause the symptoms of autism. Because most of our knowledge comes from data in which children are at rest, we do not know how connectivity changes directly lead to autistic behaviors, such as impaired gestures. When typically developing children produced complex movements, connectivity decreased between brain regions. In children with autism, connectivity increased. It may be that behavior-related changes in brain connectivity are more important than absolute differences in connectivity in autism.

In this study, we aim to automate the sleep stage scoring process of overnight polysomnography (PSG) data while adhering to expert-based rules. We developed a sleep stage scoring algorithm utilizing the generalized linear modelling (GLM) framework and extracted features from electroencephalogram (EEG), electromyography (EMG) and electrooculogram (EOG) signals based on predefined rules of the American Academy of Sleep Medicine (AASM) Manual for Scoring Sleep. Specifically, features were computed in 30-s epochs in the time and frequency domains of the signals and were then used to model the probability of an epoch being in each of five sleep stages: N3, N2, N1, REM or Wake. Finally, each epoch was assigned to a sleep stage based on model predictions. The algorithm was trained and tested on PSG data from 38 healthy individuals with no reported sleep disturbances. The overall scoring accuracy reached on the test set was 81.50 ± 1.14% (Cohen's kappa, κ = 0.73 ± 0.02 ). The test set results were highly comparable to the training set, indicating robustness of the algorithm. Furthermore, our algorithm was compared to three well-known commercialized sleep-staging tools and achieved higher accuracies than all of them. Our results suggest that automatic classification is highly consistent with visual scoring. We conclude that our algorithm can reproduce the judgement of a scoring expert and is also highly interpretable. This tool can assist visual scorers to speed up their process (from hours to minutes) and provides a method for a more robust, quantitative, reproducible and cost-effective PSG evaluation, supporting assessment of sleep and sleep disorders.

Abnormal functional connectivity was reported as one of the underlying characteristics of autism spectrum disorder (ASD). Considering the motor deficits in ASD, we utilized praxis to investigate the neural mechanisms of ASD during motor task. Since the previous functional connectivity studies reported divergent results, we explored the properties of the functional connectivity using graph metrics to address brain organization alterations of ASD. We proposed the use of eLORETA to investigate the cortical connectivity during praxis based on a cohort of 45 high-functioning ASD (HFA) children and 45 typically developing (TD) children. The between-group comparison revealed higher clustering coefficient and lower global efficiency for HFA relative to TD while the between-phase comparison suggested decreasing global efficiency, increasing characteristic path length for TD. Nodal metrics exhibited significant differences between groups in frontal and occipital regions. These regions also showed significant changes of nodal metrics and connection strengths between baseline and praxis execution for TD. However, there were no significant changes in global, nodal metrics and connection strengths between phases for HFA. Our study suggested that cortical connectivity in ASD exhibited lower overall efficiency and a deficit in reorganization, which deepens the understanding of abnormal brain organization in ASD.

The chapters in this Handbook reveal the breadth of brilliant imaging and analysis techniques designed to fulfill the mandate of cognitive neuroscience: to understand how anatomical structures and physiological processes in the brain cause typical and atypical behavior. Yet merely producing data from the latest imaging method is insufficient to truly achieve this goal. We also need a mental toolbox that contains methods of inference that allow us to derive true scientific explanation from these data. Causal inference is not easy in the human brain, where we are limited primarily to observational data and our methods of experimental perturbation in the service of causal explanation are limited. As a case study, we reverse engineer one of the most influential accounts of a neuropsychiatric disorder that is derived from observational imaging data: the connectivity theories of autism spectrum disorder (ASD). We take readers through an approach of first considering all possible causal paths that are allowed by preliminary imaging-behavioral correlations. By progressively sharpening the specificity of the measures and brain/behavioral constructs, we iteratively chip away at this space of allowable causal paths, like the sculptor chipping away the excess marble to reveal the statue. To assist in this process, we consider how current imaging methods that are lumped together under the rubric of “connectivity” may actually offer a differentiated set of connectivity constructs that can more specifically relate notions of information transmission in the mind to the physiology of the brain.

IntroductionChildren with disorders of consciousness (DOC) represent the highest end of the acquired brain injury (ABI) severity spectrum for survivors and experience a multitude of functional impairments. Current clinical management in DOC uses behavioural evaluation measures and interventions that fail to (1) describe the physiological consequences of ABI and (2) elicit functional gains. In paediatric DOC, there is a critical need to develop evidence-based interventions to promote recovery of basic responses to improve rehabilitation and aid decision-making for medical teams and caregivers. The purpose of this investigation is to examine the safety, tolerability and feasibility of transcranial direct current stimulation (tDCS) in children with DOC.Methods and analysisThis study is an open-label dose escalation trial evaluating the safety, tolerability and feasibility of tDCS in 10 children (5–17 years) receiving inpatient rehabilitation for DOC. This study will follow a modified rule-based design, allowing for intrapatient escalation, where a cohort of patients will be assigned to an initial tDCS current of 0.5 or 1 mA based on participant’s head circumference and according to the safety data available in other paediatric populations. The subsequent assignment of increased current (1 or 2 mA) according to the prespecified rules will be based on the clinical observation of adverse events in the patients. The study will include up to three, 20 min sessions of anodal tDCS (sham, 0.5 or 1 mA, 1 or 2 mA) applied over the dorsolateral prefrontal cortex. The primary outcomes are adverse events, pain associated with tDCS and intolerable disruption of inpatient care. Secondary outcomes are changes in electroencephalography (EEG) phase-locking and event-related potential components and the Coma Recovery Scale-Revised total score from prestimulation to poststimulation.Ethics and disseminationThe Johns Hopkins IRB (#IRB00174966) approved this study. Trial results will be disseminated through journals and conferences.Registration numberNCT03618849.

Children with autism spectrum disorders (ASD) have long been known to have deficits in the performance of praxis gestures; these motor deficits also correlate with social and communicative deficits. To date, the precise nature of the errors involved in praxis has not been clearly mapped out. Based on observations of individuals with ASD performing gestures, we hypothesized that the simultaneous execution of multiple movement elements is especially impaired in affected children. We examined 25 school-aged participants with ASD and 25 age-matched controls performing seven simultaneous gestures that required the concurrent performance of movement elements and nine serial gestures, in which all elements were performed serially. There was indeed a group × gesture-type interaction (P

Previous research has demonstrated distinct neural correlates for maintenance of abstract, relational versus concrete, sensory information in working memory (WM). Storage of spatial relations in WM results in suppression of posterior sensory regions, which suggests that sensory information is task-irrelevant when relational representations are maintained in WM. However, the neural mechanisms by which abstract representations are derived from sensory information remain unclear. Here, using electroencephalography, we investigated the role of alpha oscillations in deriving spatial relations from a sensory stimulus and maintaining them in WM. Participants encoded two locations into WM, then after an initial maintenance period, a cue indicated whether to convert the spatial information to another sensory representation or to a relational representation. Results revealed that alpha power increased over posterior electrodes when sensory information was converted to a relational representation, but not when the information was converted to another sensory representation. Further, alpha phase synchrony between posterior and frontal regions increased for relational compared to sensory trials during the maintenance period. These results demonstrate that maintaining spatial relations and locations in WM rely on distinct neural oscillatory patterns.

Investment in drug development for neurodevelopmental disorders has suffered from recent failures in clinical trials that were based on promising preclinical findings. Here, we discuss development and validation of translational biomarkers of neurodevelopmental disorders that can enable more informative clinical experiments and translational success in these diseases. Investment in drug development for neurodevelopmental disorders has suffered from recent failures in clinical trials that were based on promising preclinical findings. Here, we discuss development and validation of translational biomarkers of neurodevelopmental disorders that can enable more informative clinical experiments and translational success in these diseases.

Epilepsy is known to occur in a higher-than-expected proportion of individuals with autism spectrum disorders (ASDs). Prior studies of this heterogeneous disorder have suggested that intelligence quotient (IQ) may drive this relationship. Because intellectual disability (ID) is, independently of ASD, a risk factor for epilepsy, current literature calls into question the long-understood unique relationship between ASD and epilepsy. Second, data have been unclear about whether developmental regression in ASD is associated with epilepsy. Using two cohorts from an online research registry, totaling 6,975 children with ASD, we examined the independent role of four ASD severity measures in driving the relationship with epilepsy: ID, language impairment, core ASD symptom severity, and motor dysfunction, controlling for two known relevant factors: age and sex. We also examined whether developmental regression and epilepsy have an independent statistical link. All four ASD severity factors showed independent statistical associations with epilepsy in one cohort, and three in the other. ID showed the largest relative risk (RR) in both cohorts. Effect sizes were modest. Regression similarly showed an independent statistical association with epilepsy, but with small effect size. Similar to previous work, ID showed the greatest contribution to RR for epilepsy among children with ASD. However, other ASD severity markers showed statistical associations, demonstrating that the ASD-epilepsy association is not reducible to the effect of ID. Inconsistencies in the literature may be due to underpowered studies, yet moving forward with larger-n studies, clinical significance and scientific relevance may be dictated by effect size and not merely statistical significance. Autism Res 2019, 12: 1251-1259. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Epilepsy is known to occur more often in individuals with autism spectrum disorders (ASDs) than is the case in the general population. The association between ASD and epilepsy is of interest because studying the two disorders in combination may help advance our understanding of genetic, molecular, and cellular mechanisms-as well as therapies-for both. Recent studies have suggested that intelligence quotient (IQ) alone in individuals with ASD may account for the increased prevalence of epilepsy. However, our approach was to look at a range of severity factors relevant to ASD and to look for correlations between each severity factor and epilepsy, within two large samples of children with ASD. In summary, we found that each severity factor-presence of intellectual disability, presence of language atypicalities, ASD-specific symptoms severity, and presence of motor issues-independently predicted a small increased risk for epilepsy, countering the argument that IQ alone is a risk factor. We also examined whether epilepsy is associated with developmental regression. Although severe epilepsy syndromes such as Landau-Kleffner syndrome are known to cause autistic-like symptoms following developmental regression, there is controversy about whether other forms of epilepsy are associated with the more common developmental regression seen in many young children with epilepsy. Indeed, we found a small association between epilepsy and developmental regression.

Overnight polysomnography (PSG) is the gold standard tool used to characterize sleep and for diagnosing sleep disorders. PSG is a non-invasive procedure that collects various physiological data which is then scored by sleep specialists who assign a sleep stage to every 30-second window of the data according to predefined scoring rules. In this study, we aimed to automate the process of sleep stage scoring of overnight PSG data while adhering to expert-based rules. We developed an algorithm utilizing a likelihood ratio decision tree classifier and extracted features from EEG, EMG and EOG signals based on predefined rules of the American Academy of Sleep Medicine Manual. Specifically, features were computed in 30-second epochs in the time and the frequency domains of the signals and used as inputs to the classifier which assigned each epoch to one of five possible stages: N3, N2, N1, REM or Wake. The algorithm was trained and tested on PSG data from 38 healthy individuals with no reported sleep disturbances. The overall scoring accuracy was 80.70% on the test set, which was comparable to the training set. Our results imply that the automatic classification is highly robust, fast, consistent with visual scoring and is highly interpretable.

Praxis, the performance of complex motor gestures, is crucial to the development of motor and social/communicative capacities. Praxis relies on a network consisting of inferior parietal and premotor regions, particularly on the left, and is thought to require transformation of spatio-temporal representations (parietal) into movement sequences (premotor).We examined praxis network dynamics by measuring EEG effective connectivity while healthy subjects performed a praxis task.Propagation from parietal to frontal regions was not statistically greater on the left than the right. However, propagation from left parietal regions to all other regions was significantly greater during gesture preparation than execution. Moreover, during gesture preparation only, propagation from the left parietal region to bilateral frontal regions was greater than reciprocal propagations to the left parietal region. This directional specificity was not observed for the right parietal region.These findings represent direct electrophysiological evidence for directionally predominant propagation in left frontal-parietal networks during praxis behavior, which may reflect neural mechanisms by which representations in the human brain select appropriate motor sequences for subsequent execution.In addition to bolstering the classic view of praxis network function, these results also demonstrate the relevance of additional information provided by directed connectivity measures.

There has been an explosion in the development of electroencephalogram (EEG)-based biomarkers and clinical tests. This upsurge is likely due to an increase in therapies rooted in biological mechanisms rather than behavioral descriptions, as well as to the democratization of computational power and the lower cost of EEG compared with competing methodologies. This increase in motivation and opportunity demands an increased responsibility for proper validation studies. Fields including laboratory medicine and psychometrics have paved the way for rigorous validation methodology. This chapter reviews a systematic methodology for biomarker/clinical test validation, translating approaches from other fields to the specific characteristics of EEG-based metrics. A checklist is provided to help readers design high-quality diagnostic validation studies of EEG-based biomarkers.

Working memory (WM) is the ability to maintain and manipulate task-relevant information in the absence of sensory input. While its improvement through training is of great interest, the degree to which WM training transfers to untrained WM tasks (near transfer) and other untrained cognitive skills (far transfer) remains debated and the mechanism(s) underlying transfer are unclear. Here we hypothesized that a critical feature of dual n-back training is its reliance on maintaining relational information in WM. In experiment 1, using an individual differences approach, we found evidence that performance on an n-back task was predicted by performance on a measure of relational WM (i.e., WM for vertical spatial relationships independent of absolute spatial locations), whereas the same was not true for a complex span WM task. In experiment 2, we tested the idea that reliance on relational WM is critical to produce transfer from n-back but not complex span task training. Participants completed adaptive training on either a dual n-back task, a symmetry span task, or on a non-WM active control task. We found evidence of near transfer for the dual n-back group; however, far transfer to a measure of fluid intelligence did not emerge. Recording EEG during a separate WM transfer task, we examined group-specific, training-related changes in alpha power, which are proposed to be sensitive to WM demands and top-down modulation of WM. Results indicated that the dual n-back group showed significantly greater frontal alpha power after training compared to before training, more so than both other groups. However, we found no evidence of improvement on measures of relational WM for the dual n-back group, suggesting that near transfer may not be dependent on relational WM. These results suggest that dual n-back and complex span task training may differ in their effectiveness to elicit near transfer as well as in the underlying neural changes they facilitate.

Decreasing biomedical research support over the past decade has driven many talented young scientists to seek careers outside academia. In 2011, the Department of Neurology at Johns Hopkins University School of Medicine developed an internal grant review program (IGRP) to systematically review career development awards (CDAs) and research grants (e.g., R01s) for junior investigators prior to NIH submission. With IGRP implementation, we observed significant increases in the number of CDAs and R-grants awarded to junior investigators. Thus, internal grant review is an effective means for supporting junior faculty and help them retain their research roles within academia.

Objective: We sought to examine the prevalence of EEG abnormalities in Smith-Lemli-Opitz syndrome (SLOS) as well as the relationship between interictal epileptiform discharges (IEDs) and within-subject variations in attentional symptom severity. Methods: In the context of a clinical trial for SLOS, we performed cross-sectional and repeated-measure observational studies of the relationship between EEG findings and cognitive/behavioral factors on 23 children (aged 4–17 years). EEGs were reviewed for clinical abnormalities, including IEDs, by readers blinded to participants9 behavioral symptoms. Between-group differences in baseline characteristics of participants with and without IEDs were analyzed. Within-subject analyses examined the association between the presence of IEDs and changes in attention-deficit/hyperactivity disorder (ADHD) symptoms. Results: Of 85 EEGs, 43 (51%) were abnormal, predominantly because of IEDs. Only one subject had documented clinical seizures. IEDs clustered in 13 subjects (57%), whereas 9 subjects (39%) had EEGs consistently free of IEDs. While there were no significant group differences in sex, age, intellectual disability, language level, or baseline ADHD symptoms, autistic symptoms tended to be more prevalent in the “IED” group (according to Autism Diagnostic Observation Schedule–2 criteria). Within individuals, the presence of IEDs on a particular EEG predicted, on average, a 27% increase in ADHD symptom severity. Conclusions: Epileptiform discharges are common in SLOS, despite a relatively low prevalence of epilepsy. Fluctuations in the presence of epileptiform discharges within individual children with a developmental disability syndrome may be associated with fluctuations in ADHD symptomatology, even in the absence of clinical seizures.

Attention can modulate processing of visual input according to task-relevant features, even as early as approximately 100 ms after stimulus presentation. In the present study, event-related potential and behavioral data revealed that inhibition of distractor features, rather than activation of target features, is the primary driver of early feature-based selection in human observers. This discovery of inhibition consistent with task goals during early visual processing suggests that inhibition plays a much larger role at an earlier stage of target selection than previously recognized. It also highlights the importance of understanding the role of inhibition (in addition to activation) in attention.

Geschildert wird der Weg des Autors auf Basis der manuellen Medizin in die osteopathische Medizin in einer Zeit, als diese nur in limitierten Moglichkeiten und durch das Engagement einzelner Manualmediziner in Deutschland moglich war. Ein Modell fur Verkettungssyndrome wird anhand der Arbeiten von M. Forte mit dessen Definitionen von Kompensation, Adaptation und Dekompensation vorgestellt. Darauf aufbauend werden Uberlegungen zur Wirkweise der osteopathischen Medizin angestellt und diese in den Kontext der gegenwartigen kontroversen Diskussion um osteopathische Verfahren und osteopathische Medizin gestellt.

INTRODUCTION: Patterns and predictors of recovery from encephalitis are poorly understood. METHODS: This study examined functional status and reviewed charts of all children who presented to a pediatric inpatient rehabilitation facility with encephalitis between 1996 and 2010. Functional status at admission and discharge from inpatient rehabilitation was evaluated using the Functional Independence Measure for Children (WeeFIM) Self-care, Mobility, Cognitive, and Total Developmental Functional Quotient scores (DFQ, % of age-appropriate function). Charts were reviewed to characterize key clinical features and findings. RESULTS: Of the 13 children identified, the mean age was 9 years (range 5–16) with 54% males. Mean WeeFIM Total DFQ at admission was 37 (range: 15–90) and at discharge was 64 (range: 16–96). Average change in WeeFIM Total DFQ from admission to discharge was 26.7 (range 0–55, p< 0.001). WeeFIM domain scores improved between admission and discharge (Self-Care: p< 0.001, Cognition: p< 0.01, Mobility: p< 0.001). Eleven children displayed significant impairments in functional skills, defined as DFQ of 85, at discharge. Key clinical features and findings were diverse and not related to functional outcome. CONCLUSIONS: Results suggest that significant functional improvement in children with encephalitis occurs during inpatient rehabilitation. Further research is necessary to identify predictors of outcome in children with encephalitis.