Neonatal Autonomic Regulation as a Predictor of Autism Spectrum Disorder in Very Preterm Infants.

Infants born preterm are at a significantly higher likelihood of having autism spectrum disorder (ASD). Preterm birth and ASD are both associated with neurological differences, notably autonomic nervous system (ANS) dysfunction, pointing to preterm ANS dysfunction as a potential pathway to ASD, particularly in VPT infants. In this study, a subset of very preterm (VPT) infants enrolled in a large, multisite clinical trial were enrolled in this study at birth (N=20). Continuous measures of minute-by-minute thermal gradients, defined by the difference between central and peripheral temperatures, and hour-by-hour abnormal heart rate characteristics (HRCs) were collected from birth-28 days (>40,000 samples/infant). Following NICU discharge, standardized measures of cognition, language, and motor skills were collected at adjusted ages 6, 9, and 12 months. At 12 months, assessments of social communication and early ASD symptoms were administered. Results suggest significant ASD concerns for half of the sample by 12 months of age. Neonatal abnormal HRCs were strongly associated with 12-month ASD symptoms (r=0.81, p<.01), as was birth gestational age (GA), birth weight (BW), and abnormal negative thermal gradients. ANS measures collected in the first month of neonatal life, more than a year prior to the ASD evaluation, were surprisingly strong predictors of ASD. This study highlights complementary ANS measures that describe how ANS dysfunction, likely resulting from an imbalance between the parasympathetic and sympathetic systems, may impact very early regulatory processes for neonates who later develop ASD. This finding offers a promising avenue for researching ANS-related etiological mechanisms and biomarkers of ASD.

EEG functional connectivity in infants at elevated familial likelihood for autism spectrum disorder.

BACKGROUND: Many studies have reported that autism spectrum disorder (ASD) is associated with atypical structural and functional connectivity. However, we know relatively little about the development of these differences in infancy. METHODS: We used a high-density electroencephalogram (EEG) dataset pooled from two independent infant sibling cohorts, to characterize such neurodevelopmental deviations during the first years of life. EEG was recorded at 6 and 12 months of age in infants at typical (N = 92) or elevated likelihood for ASD (N = 90), determined by the presence of an older sibling with ASD. We computed the functional connectivity between cortical sources of EEG during video watching using the corrected imaginary part of phase-locking values. RESULTS: Our main analysis found no significant association between functional connectivity and ASD, showing only significant effects for age, sex, age-sex interaction, and site. Given these null results, we performed an exploratory analysis and observed, at 12 months, a negative correlation between functional connectivity and ADOS calibrated severity scores for restrictive and repetitive behaviors (RRB). LIMITATIONS: The small sample of ASD participants inherent to sibling studies limits diagnostic group comparisons. Also, results from our secondary exploratory analysis should be considered only as potential relationships to further explore, given their increased vulnerability to false positives. CONCLUSIONS: These results are inconclusive concerning an association between EEG functional connectivity and ASD in infancy. Exploratory analyses provided preliminary support for a relationship between RRB and functional connectivity specifically, but these preliminary observations need corroboration on larger samples.

Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances.

Patients with neurocognitive disorders often battle sleep disturbances. Kynurenic acid is a tryptophan metabolite of the kynurenine pathway implicated in the pathology of these illnesses. Modest increases in kynurenic acid, an antagonist at glutamatergic and cholinergic receptors, result in cognitive impairments and sleep dysfunction. We explored the hypothesis that inhibition of the kynurenic acid synthesising enzyme, kynurenine aminotransferase II, may alleviate sleep disturbances. At the start of the light phase, adult male and female Wistar rats received systemic injections of either: (i) vehicle; (ii) kynurenine (100 mg kg-1 ; i.p.); (iii) the kynurenine aminotransferase II inhibitor, PF-04859989 (30 mg kg-1 ; s.c.); or (iv) PF-04859989 and kynurenine in combination. Kynurenine and kynurenic acid levels were evaluated in the plasma and brain. Separate animals were implanted with electroencephalogram and electromyogram telemetry devices to record polysomnography, and evaluate the vigilance states wake, rapid eye movement sleep and non-rapid eye movement sleep following each treatment. Kynurenine challenge increased brain kynurenic acid and resulted in reduced rapid eye movement sleep duration, non-rapid eye movement sleep delta power and sleep spindles. PF-04859989 reduced brain kynurenic acid formation when given prior to kynurenine, prevented disturbances in rapid eye movement sleep and sleep spindles, and enhanced non-rapid eye movement sleep. Our findings suggest that reducing kynurenic acid in conditions where the kynurenine pathway is activated may serve as a potential strategy for improving sleep dynamics.

ECG Recordings as Predictors of Very Early Autism Likelihood: A Machine Learning Approach.

In recent years, there has been a rise in the prevalence of autism spectrum disorder (ASD). The diagnosis of ASD requires behavioral observation and standardized testing completed by highly trained experts. Early intervention for ASD can begin as early as 1-2 years of age, but ASD diagnoses are not typically made until ages 2-5 years, thus delaying the start of intervention. There is an urgent need for non-invasive biomarkers to detect ASD in infancy. While previous research using physiological recordings has focused on brain-based biomarkers of ASD, this study investigated the potential of electrocardiogram (ECG) recordings as an ASD biomarker in 3-6-month-old infants. We recorded the heart activity of infants at typical and elevated familial likelihood for ASD during naturalistic interactions with objects and caregivers. After obtaining the ECG signals, features such as heart rate variability (HRV) and sympathetic and parasympathetic activities were extracted. Then we evaluated the effectiveness of multiple machine learning classifiers for classifying ASD likelihood. Our findings support our hypothesis that infant ECG signals contain important information about ASD familial likelihood. Amongthe various machine learning algorithms tested, KNN performed best according to sensitivity (0.70 ± 0.117), F1-score (0.689 ± 0.124), precision (0.717 ± 0.128), accuracy (0.70 ± 0.117, p-value = 0.02), and ROC (0.686 ± 0.122, p-value = 0.06). These results suggest that ECG signals contain relevant information about the likelihood of an infant developing ASD. Future studies should consider the potential of information contained in ECG, and other indices of autonomic control, for the development of biomarkers of ASD in infancy.

Model-Driven Analysis of ECG Using Reinforcement Learning.

Modeling is essential to better understand the generative mechanisms responsible for experimental observations gathered from complex systems. In this work, we are using such an approach to analyze the electrocardiogram (ECG). We present a systematic framework to decompose ECG signals into sums of overlapping lognormal components. We use reinforcement learning to train a deep neural network to estimate the modeling parameters from an ECG recorded in babies from 1 to 24 months of age. We demonstrate this model-driven approach by showing how the extracted parameters vary with age. From the 751,510 PQRST complexes modeled, 82.7% provided a signal-to-noise ratio that was sufficient for further analysis (>5 dB). After correction for multiple tests, 10 of the 24 modeling parameters exhibited statistical significance below the 0.01 threshold, with absolute Kendall rank correlation coefficients in the [0.27, 0.51] range. These results confirm that this model-driven approach can capture sensitive ECG parameters. Due to its physiological interpretability, this approach can provide a window into latent variables which are important for understanding the heart-beating process and its control by the autonomous nervous system.

EEG functional connectivity in infants at elevated familial risk for autism spectrum disorder.

Background: Many studies have reported that autism spectrum disorder (ASD) is associated with atypical structural and functional connectivity. However, relatively little is known about the development of these differences in infancy and on how trajectories may vary between sexes. Methods: We used the International Infant EEG Platform (EEG-IP), a high-density electroencephalogram (EEG) dataset pooled from two independent infant sibling cohorts, to characterize such neurodevelopmental deviations during the first years of life. EEG was recorded at 6, 12, and 18 months of age at typical (N=97) or high familial risk for ASD (N=98), determined by the presence of an older sibling with a confirmed ASD diagnosis. We computed the functional connectivity between cortical EEG sources during video watching using the corrected imaginary part of phase-locking values. Results: Our findings showed low regional specificity for group differences in functional connectivity but revealed different sex-specific trajectories between females and males in the group of high-risk infants. Specifically, functional connectivity was negatively correlated with ADOS calibrated severity scores, particularly at 12 months for the social affect score for females and for the restrictive and repetitive behaviors for males. Limitations: This study has been limited mostly due to issues related to the relatively small effective sample size inherent in sibling studies, particularly for diagnostic group comparisons. Conclusions: These results are consistent with sex differences in ASD observed in previous research and provide further insights into the role of functional connectivity in these differences.

Thalamic control of sensory processing and spindles in a biophysical somatosensory thalamoreticular circuit model of wakefulness and sleep.

Thalamoreticular circuitry plays a key role in arousal, attention, cognition, and sleep spindles, and is linked to several brain disorders. A detailed computational model of mouse somatosensory thalamus and thalamic reticular nucleus has been developed to capture the properties of over 14,000 neurons connected by 6 million synapses. The model recreates the biological connectivity of these neurons, and simulations of the model reproduce multiple experimental findings in different brain states. The model shows that inhibitory rebound produces frequency-selective enhancement of thalamic responses during wakefulness. We find that thalamic interactions are responsible for the characteristic waxing and waning of spindle oscillations. In addition, we find that changes in thalamic excitability control spindle frequency and their incidence. The model is made openly available to provide a new tool for studying the function and dysfunction of the thalamoreticular circuitry in various brain states.

Neural mechanisms of language development in infancy.

Understanding the neural processes underpinning individual differences in early language development is of increasing interest, as it is known to vary in typical development and to be quite heterogeneous in neurodevelopmental conditions. However, few studies to date have tested whether early brain measures are indicative of the developmental trajectory of language, as opposed to language outcomes at specific ages. We combined recordings from two longitudinal studies, including typically developing infants without a family history of autism, and infants with increased likelihood of developing autism (infant-siblings) (N = 191). Electroencephalograms (EEG) were recorded at 6 months, and behavioral assessments at 6, 12, 18, 24 and 36 months of age. Using a growth curve model, we tested whether absolute EEG spectral power at 6 months was associated with concurrent language abilities, and developmental change in language between 6 and 36 months. We found evidence of an association between 6-month alpha-band power and concurrent, but not developmental change in, expressive language ability in both infant-siblings and control infants. The observed association between 6-month alpha-band power and 6-month expressive language was not moderated by group status, suggesting some continuity in neural mechanisms.

Aging-Related Differences in Structural and Functional Interhemispheric Connectivity.

There is substantial evidence of age-related declines in anatomical connectivity during adulthood, with associated alterations in functional connectivity. But the relation of those functional alterations to the structural reductions is unclear. The complexities of both the structural and the functional connectomes make it difficult to determine such relationships. We pursue this question with methods, based on animal research, that specifically target the interhemispheric connections between the visual cortices. We collect t1- and diffusion-weighted imaging data from which we assess the integrity of the white matter interconnecting the bilateral visual cortices. Functional connectivity between the visual cortices is measured with electroencephalography during the presentation of drifting sinusoidal gratings that agree or conflict across hemifields. Our results show age-related reductions in the integrity of the white matter interconnecting the visual cortices, and age-related increases in the difference in functional interhemispheric lagged coherence between agreeing versus disagreeing visual stimuli. We show that integrity of the white matter in the splenium of the corpus callosum predicts the differences in lagged coherence for the agreeing versus disagreeing stimuli; and that this relationship is mediated by age. These results give new insight into the causal relationship between age and functional connectivity.

Rodent somatosensory thalamocortical circuitry: Neurons, synapses, and connectivity.

As our understanding of the thalamocortical system deepens, the questions we face become more complex. Their investigation requires the adoption of novel experimental approaches complemented with increasingly sophisticated computational modeling. In this review, we take stock of current data and knowledge about the circuitry of the somatosensory thalamocortical loop in rodents, discussing common principles across modalities and species whenever appropriate. We review the different levels of organization, including the cells, synapses, neuroanatomy, and network connectivity. We provide a complete overview of this system that should be accessible for newcomers to this field while nevertheless being comprehensive enough to serve as a reference for seasoned neuroscientists and computational modelers studying the thalamocortical system. We further highlight key gaps in data and knowledge that constitute pressing targets for future experimental work. Filling these gaps would provide invaluable information for systematically unveiling how this system supports behavioral and cognitive processes.

Structural templates for imaging EEG cortical sources in infants.

Electroencephalographic (EEG) source reconstruction is a powerful approach that allows anatomical localization of electrophysiological brain activity. Algorithms used to estimate cortical sources require an anatomical model of the head and the brain, generally reconstructed using magnetic resonance imaging (MRI). When such scans are unavailable, a population average can be used for adults, but no average surface template is available for cortical source imaging in infants. To address this issue, we introduce a new series of 13 anatomical models for subjects between zero and 24 months of age. These templates are built from MRI averages and boundary element method (BEM) segmentation of head tissues available as part of the Neurodevelopmental MRI Database. Surfaces separating the pia mater, the gray matter, and the white matter were estimated using the Infant FreeSurfer pipeline. The surface of the skin as well as the outer and inner skull surfaces were extracted using a cube marching algorithm followed by Laplacian smoothing and mesh decimation. We post-processed these meshes to correct topological errors and ensure watertight meshes. Source reconstruction with these templates is demonstrated and validated using 100 high-density EEG recordings from 7-month-old infants. Hopefully, these templates will support future studies on EEG-based neuroimaging and functional connectivity in healthy infants as well as in clinical pediatric populations.

Intracranial recordings reveal ubiquitous in-phase and in-antiphase functional connectivity between homotopic brain regions in humans.

Whether neuronal populations exhibit zero-lag (in-phase or in-antiphase) functional connectivity is a fundamental question when conceptualizing communication between cell assemblies. It also has profound implications on how we assess such interactions. Given that the brain is a delayed network due to the finite conduction velocity of the electrical impulses traveling across its fibers, the existence of long-distance zero-lag functional connectivity may be considered improbable. However, in this study, using human intracranial recordings we demonstrate that most interhemispheric connectivity between homotopic cerebral regions is zero-lagged and that this type of connectivity is ubiquitous. Volume conduction can be safely discarded as a confounding factor since it is known to drop almost completely within short interelectrode distances (<20 mm) in intracranial recordings. This finding should guide future electrophysiological connectivity studies and highlight the importance of considering the role of zero-lag connectivity in our understanding of communication between cell assemblies.

Spindles insufficiency in sleepwalkers' deep sleep.

OBJECTIVES: Sleepwalkers have consistently shown N3 sleep discontinuity, especially after sleep deprivation. In healthy subjects, sleep spindles activity has been positively correlated to sleep stability. We aimed to compare spindles density during N3 sleep between sleepwalkers and healthy controls. METHODS: Two cohorts of 10 and 21 adult sleepwalkers respectively controlled with 10 and 18 healthy volunteers underwent one baseline and one recovery sleep recording after 38h (cohort 1) and 25h (cohort 2) of sleep deprivation. For the two recordings, we performed an automatic detection of spindles (11-16Hz) from EEG signal during N3 sleep, restricted to the first sleep cycle and repeated for all cycles. For better interpretation of results, we extended the analysis to N2 sleep and we also measured the density of slow waves oscillation (SWO) (0.5-4Hz) during the same periods. RESULTS: Compared to controls, sleepwalkers showed significantly lower spindle densities during N3 sleep considering the first sleep cycle (both cohorts) or all cycles (cohort 1). SWO densities did not differ (cohort 1) or were lower (cohort 2) for sleepwalkers. The effect of sleep deprivation did not interact with the effect of group on spindles and SWO densities. CONCLUSION: This work suggests that the instability of N3 sleep inherent to sleepwalkers may be underpinned by a specific alteration of spindles activity.

Experimentally-constrained biophysical models of tonic and burst firing modes in thalamocortical neurons.

Somatosensory thalamocortical (TC) neurons from the ventrobasal (VB) thalamus are central components in the flow of sensory information between the periphery and the cerebral cortex, and participate in the dynamic regulation of thalamocortical states including wakefulness and sleep. This property is reflected at the cellular level by the ability to generate action potentials in two distinct firing modes, called tonic firing and low-threshold bursting. Although the general properties of TC neurons are known, we still lack a detailed characterization of their morphological and electrical properties in the VB thalamus. The aim of this study was to build biophysically-detailed models of VB TC neurons explicitly constrained with experimental data from rats. We recorded the electrical activity of VB neurons (N = 49) and reconstructed morphologies in 3D (N = 50) by applying standardized protocols. After identifying distinct electrical types, we used a multi-objective optimization to fit single neuron electrical models (e-models), which yielded multiple solutions consistent with the experimental data. The models were tested for generalization using electrical stimuli and neuron morphologies not used during fitting. A local sensitivity analysis revealed that the e-models are robust to small parameter changes and that all the parameters were constrained by one or more features. The e-models, when tested in combination with different morphologies, showed that the electrical behavior is substantially preserved when changing dendritic structure and that the e-models were not overfit to a specific morphology. The models and their analysis show that automatic parameter search can be applied to capture complex firing behavior, such as co-existence of tonic firing and low-threshold bursting over a wide range of parameter sets and in combination with different neuron morphologies.

Visbrain: A Multi-Purpose GPU-Accelerated Open-Source Suite for Multimodal Brain Data Visualization.

We present Visbrain, a Python open-source package that offers a comprehensive visualization suite for neuroimaging and electrophysiological brain data. Visbrain consists of two levels of abstraction: (1) objects which represent highly configurable neuro-oriented visual primitives (3D brain, sources connectivity, etc.) and (2) graphical user interfaces for higher level interactions. The object level offers flexible and modular tools to produce and automate the production of figures using an approach similar to that of Matplotlib with subplots. The second level visually connects these objects by controlling properties and interactions through graphical interfaces. The current release of Visbrain (version 0.4.2) contains 14 different objects and three responsive graphical user interfaces, built with PyQt: Signal, for the inspection of time-series and spectral properties, Brain for any type of visualization involving a 3D brain and Sleep for polysomnographic data visualization and sleep analysis. Each module has been developed in tight collaboration with end-users, i.e., primarily neuroscientists and domain experts, who bring their experience to make Visbrain as transparent as possible to the recording modalities (e.g., intracranial EEG, scalp-EEG, MEG, anatomical and functional MRI). Visbrain is developed on top of VisPy, a Python package providing high-performance 2D and 3D visualization by leveraging the computational power of the graphics card. Visbrain is available on Github and comes with a documentation, examples, and datasets (http://visbrain.org).

A Text Mining Pipeline Using Active and Deep Learning Aimed at Curating Information in Computational Neuroscience.

The curation of neuroscience entities is crucial to ongoing efforts in neuroinformatics and computational neuroscience, such as those being deployed in the context of continuing large-scale brain modelling projects. However, manually sifting through thousands of articles for new information about modelled entities is a painstaking and low-reward task. Text mining can be used to help a curator extract relevant information from this literature in a systematic way. We propose the application of text mining methods for the neuroscience literature. Specifically, two computational neuroscientists annotated a corpus of entities pertinent to neuroscience using active learning techniques to enable swift, targeted annotation. We then trained machine learning models to recognise the entities that have been identified. The entities covered are Neuron Types, Brain Regions, Experimental Values, Units, Ion Currents, Channels, and Conductances and Model organisms. We tested a traditional rule-based approach, a conditional random field and a model using deep learning named entity recognition, finding that the deep learning model was superior. Our final results show that we can detect a range of named entities of interest to the neuroscientist with a macro average precision, recall and F1 score of 0.866, 0.817 and 0.837 respectively. The contributions of this work are as follows: 1) We provide a set of Named Entity Recognition (NER) tools that are capable of detecting neuroscience entities with performance above or similar to prior work. 2) We propose a methodology for training NER tools for neuroscience that requires very little training data to get strong performance. This can be adapted for any sub-domain within neuroscience. 3) We provide a small corpus with annotations for multiple entity types, as well as annotation guidelines to help others reproduce our experiments.

Nicotine increases sleep spindle activity.

Studies have shown that both nicotine and sleep spindles are associated with enhanced memorisation. Further, a few recent studies have shown how cholinergic input through nicotinic and muscarinic receptors can trigger or modulate sleep processes in general, and sleep spindles in particular. To better understand the interaction between nicotine and sleep spindles, we compared in a single blind randomised study the characteristics of sleep spindles in 10 healthy participants recorded for 2 nights, one with a nicotine patch and one with a sham patch. We investigated differences in sleep spindle duration, amplitude, intra-spindle oscillation frequency and density (i.e. spindles per min). We found that under nicotine, spindles are more numerous (average increase: 0.057 spindles per min; 95% confidence interval: [0.025-0.089]; p = .0004), have higher amplitude (average amplification: 0.260 µV; confidence interval: [0.119-0.402]; p = .0032) and last longer (average lengthening: 0.025 s; confidence interval: [0.017-0.032]; p = 2.7e-11). These results suggest that nicotine can increase spindle activity by acting on nicotinic acetylcholine receptors, and offer an attractive hypothesis for common mechanisms that may support memorisation improvements previously reported to be associated with nicotine and sleep spindles.

Sleep: An Open-Source Python Software for Visualization, Analysis, and Staging of Sleep Data.

We introduce Sleep, a new Python open-source graphical user interface (GUI) dedicated to visualization, scoring and analyses of sleep data. Among its most prominent features are: (1) Dynamic display of polysomnographic data, spectrogram, hypnogram and topographic maps with several customizable parameters, (2) Implementation of several automatic detection of sleep features such as spindles, K-complexes, slow waves, and rapid eye movements (REM), (3) Implementation of practical signal processing tools such as re-referencing or filtering, and (4) Display of main descriptive statistics including publication-ready tables and figures. The software package supports loading and reading raw EEG data from standard file formats such as European Data Format, in addition to a range of commercial data formats. Most importantly, Sleep is built on top of the VisPy library, which provides GPU-based fast and high-level visualization. As a result, it is capable of efficiently handling and displaying large sleep datasets. Sleep is freely available (http://visbrain.org/sleep) and comes with sample datasets and an extensive documentation. Novel functionalities will continue to be added and open-science community efforts are expected to enhance the capacities of this module.

Is functional brain connectivity atypical in autism? A systematic review of EEG and MEG studies.

BACKGROUND: Although it is well recognized that autism is associated with altered patterns of over- and under-connectivity, specifics are still a matter of debate. Little has been done so far to synthesize available literature using whole-brain electroencephalography (EEG) and magnetoencephalography (MEG) recordings. OBJECTIVES: 1) To systematically review the literature on EEG/MEG functional and effective connectivity in autism spectrum disorder (ASD), 2) to synthesize and critically appraise findings related with the hypothesis that ASD is characterized by long-range underconnectivity and local overconnectivity, and 3) to provide, based on the literature, an analysis of tentative factors that are likely to mediate association between ASD and atypical connectivity (e.g., development, topography, lateralization). METHODS: Literature reviews were done using PubMed and PsychInfo databases. Abstracts were screened, and only relevant articles were analyzed based on the objectives of this paper. Special attention was paid to the methodological characteristics that could have created variability in outcomes reported between studies. RESULTS: Our synthesis provides relatively strong support for long-range underconnectivity in ASD, whereas the status of local connectivity remains unclear. This observation was also mirrored by a similar relationship with lower frequencies being often associated with underconnectivity and higher frequencies being associated with both under- and over-connectivity. Putting together these observations, we propose that ASD is characterized by a general trend toward an under-expression of lower-band wide-spread integrative processes compensated by more focal, higher-frequency, locally specialized, and segregated processes. Further investigation is, however, needed to corroborate the conclusion and its generalizability across different tasks. Of note, abnormal lateralization in ASD, specifically an elevated left-over-right EEG and MEG functional connectivity ratio, has been also reported consistently across studies. CONCLUSIONS: The large variability in study samples and methodology makes a systematic quantitative analysis (i.e. meta-analysis) of this body of research impossible. Nevertheless, a general trend supporting the hypothesis of long-range functional underconnectivity can be observed. Further research is necessary to more confidently determine the status of the hypothesis of short-range overconnectivity. Frequency-band specific patterns and their relationships with known symptoms of autism also need to be further clarified.