Neural oscillations track recovery of consciousness in acute traumatic brain injury patients.

Electroencephalography (EEG), easily deployed at the bedside, is an attractive modality for deriving quantitative biomarkers of prognosis and differential diagnosis in severe brain injury and disorders of consciousness (DOC). Prior work by Schiff has identified four dynamic regimes of progressive recovery of consciousness defined by the presence or absence of thalamically-driven EEG oscillations. These four predefined categories (ABCD model) relate, on a theoretical level, to thalamocortical integrity and, on an empirical level, to behavioral outcome in patients with cardiac arrest coma etiologies. However, whether this theory-based stratification of patients might be useful as a diagnostic biomarker in DOC and measurably linked to thalamocortical dysfunction remains unknown. In this work, we relate the reemergence of thalamically-driven EEG oscillations to behavioral recovery from traumatic brain injury (TBI) in a cohort of N = 38 acute patients with moderate-to-severe TBI and an average of 1 week of EEG recorded per patient. We analyzed an average of 3.4 hr of EEG per patient, sampled to coincide with 30-min periods of maximal behavioral arousal. Our work tests and supports the ABCD model, showing that it outperforms a data-driven clustering approach and may perform equally well compared to a more parsimonious categorization. Additionally, in a subset of patients (N = 11), we correlated EEG findings with functional magnetic resonance imaging (fMRI) connectivity between nodes in the mesocircuit-which has been theoretically implicated by Schiff in DOC-and report a trend-level relationship that warrants further investigation in larger studies.

Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.

Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.

Motion Coherence and Luminance Contrast Interact in Driving Visual Gamma-Band Activity.

Synchronized neuronal population activity in the gamma-frequency range (>30 Hz) correlates with the bottom-up drive of various visual features. It has been hypothesized that gamma-band synchronization enhances the gain of neuronal representations, yet evidence remains sparse. We tested a critical prediction of the gain hypothesis, which is that features that drive synchronized gamma-band activity interact super-linearly. To test this prediction, we employed whole-head magnetencephalography in human subjects and investigated if the strength of visual motion (motion coherence) and luminance contrast interact in driving gamma-band activity in visual cortex. We found that gamma-band activity (64-128 Hz) monotonically increased with coherence and contrast, while lower frequency activity (8-32 Hz) decreased with both features. Furthermore, as predicted for a gain mechanism, we found a multiplicative interaction between motion coherence and contrast in their joint drive of gamma-band activity. The lower frequency activity did not show such an interaction. Our findings provide evidence that gamma-band activity acts as a cortical gain mechanism that nonlinearly combines the bottom-up drive of different visual features.

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia.

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19-37 years) underwent a randomized, three-way, cross-over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long-distance (seed-based and dual-regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10-3 ), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia-related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = -.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.

Modulation of neuronal oscillatory activity in the beta- and gamma-band is associated with current individual anxiety levels.

Human faces are among the most salient visual stimuli and act both as socially and emotionally relevant signals. Faces and especially faces with emotional expression receive prioritized processing in the human brain and activate a distributed network of brain areas reflected, e.g., in enhanced oscillatory neuronal activity. However, an inconsistent picture emerged so far regarding neuronal oscillatory activity across different frequency-bands modulated by emotionally and socially relevant stimuli. The individual level of anxiety among healthy populations might be one explanation for these inconsistent findings. Therefore, we tested the hypothesis whether oscillatory neuronal activity is associated with individual anxiety levels during perception of faces with neutral and fearful facial expressions. We recorded neuronal activity using magnetoencephalography (MEG) in 27 healthy participants and determined their individual state anxiety levels. Images of human faces with neutral and fearful expressions, and physically matched visual control stimuli were presented while participants performed a simple color detection task. Spectral analyses revealed that face processing and in particular processing of fearful faces was characterized by enhanced neuronal activity in the theta- and gamma-band and decreased activity in the beta-band in early visual cortex and the fusiform gyrus (FFG). Moreover, the individuals' state anxiety levels correlated positively with the gamma-band response and negatively with the beta response in the FFG and the amygdala. Our results suggest that oscillatory neuronal activity plays an important role in affective face processing and is dependent on the individual level of state anxiety. Our work provides new insights on the role of oscillatory neuronal activity underlying processing of faces.

Physiological processes non-linearly affect electrophysiological recordings during transcranial electric stimulation.

Transcranial electric stimulation (tES) is a promising tool to non-invasively manipulate neuronal activity in the human brain. Several studies have shown behavioral effects of tES, but stimulation artifacts complicate the simultaneous investigation of neural activity with EEG or MEG. Here, we first show for EEG and MEG, that contrary to previous assumptions, artifacts do not simply reflect stimulation currents, but that heartbeat and respiration non-linearly modulate stimulation artifacts. These modulations occur irrespective of the stimulation frequency, i.e. during both transcranial alternating and direct current stimulations (tACS and tDCS). Second, we show that, although at first sight previously employed artifact rejection methods may seem to remove artifacts, data are still contaminated by non-linear stimulation artifacts. Because of their complex nature and dependence on the subjects' physiological state, these artifacts are prone to be mistaken as neural entrainment. In sum, our results uncover non-linear tES artifacts, show that current techniques fail to fully remove them, and pave the way for new artifact rejection methods.

Measuring the cortical correlation structure of spontaneous oscillatory activity with EEG and MEG.

Power correlations of orthogonalized signals have recently been introduced for MEG as a powerful tool to non-invasively investigate functional connectivity in the human brain. Little is known about the applicability of this approach to EEG, and how compatible the results are between EEG and MEG. To address this, we systematically compared power correlations of simultaneously recorded and source co-registered 64-channel EEG and 275-channel MEG in resting human subjects. For both modalities, connectivity peaked at around 16 Hz. For this frequency range, seed-based correlation maps showed comparable patterns across modalities, with generally more distinct patterns for MEG. A brain-wide pattern correlation analysis also revealed maximum similarity around 16 Hz. Correcting for different signal-to-noise ratio (SNR) across frequencies and modalities revealed pattern correlation between modalities close to one across a broad frequency range from 1 to 32 Hz and only slightly smaller for higher frequencies. The decrease above 32 Hz likely reflected higher susceptibility to muscle artifacts for EEG than for MEG. Our results show that power correlation of orthogonalized signals is feasible for studying functional connectivity with 64-channel EEG. Furthermore, besides differences in SNR, for frequencies from about 8 to 32 Hz, EEG and MEG measure the same correlation patterns across the entire brain.

Spectral Signatures of Saccade Target Selection.

Action generation relies on a widely distributed network of brain areas. However, little is known about the spatiotemporal dynamics of neuronal activity in the network that gives rise to voluntary action in humans. Here, we used magnetoencephalography (MEG) and source analysis (n = 15, 7 female subjects) to investigate the spectral signatures of human cortical networks engaged in active and intrinsically motivated viewing behavior. We compared neuronal activity of externally cued saccades with saccades to freely chosen targets. For planning and execution of both saccade types, we found an increase in gamma band (~64-128 Hz) activity and a concurrent decrease in beta band (~12-32 Hz) activity in saccadic control areas, including the intraparietal sulcus and the frontal eye fields. Guided compared to voluntary actions were accompanied by stronger transient increases in the gamma and low frequency (<16 Hz) range immediately following the instructional cue. In contrast, action selection between competing alternatives was reflected by stronger sustained fronto-parietal gamma increases that occurred later in time and persisted until movement execution. This sustained enhancement for free target selection was accompanied by a spatially widespread reduction of lower frequency power (~8-45 Hz) in parietal and extrastriate areas. Our results suggest that neuronal population activity in the gamma frequency band in a distributed network of fronto-parietal areas reflects the intrinsically driven process of selection among competing behavioral alternatives.

Altered intrinsic neuronal interactions in the visual cortex of the blind.

In congenital blindness, the brain develops under severe sensory deprivation and undergoes remarkable plastic changes in both structure and function. Visually deprived occipital cortical regions are histologically and morphologically altered and exhibit a strikingly remodeled functional state: absolute levels of neural activity are heightened and are modulated by nonvisual sensory stimulation as well as higher cognitive processes. However, the neuronal mechanisms that underlie this altered functional state remain largely unknown. Here, we show that the visual cortex of the congenitally blind exhibits a characteristic gain in frequency-specific intrinsic neuronal interactions. We studied oscillatory activity in 11 congenitally blind humans and matched sighted control subjects with magnetoencephalography at rest. We found increased spontaneous correlations of delta band (1-3 Hz) and gamma band (76-128 Hz) oscillations across the visual cortex of the blind that were functionally coupled. Local delta phase modulated gamma amplitude. Furthermore, classical resting rhythms (8-20 Hz) were reduced in amplitude but showed no altered correlation pattern. Our results suggest that both decreased inhibition and circuit mechanisms that support active processing are intrinsic features underlying the altered functional state of the visual cortex in congenitally blind individuals.

Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis.

Correlations in spontaneous brain activity provide powerful access to large-scale organizational principles of the CNS. However, making inferences about cognitive processes requires a detailed understanding of the link between these couplings and the structural integrity of the CNS. We studied the impact of multiple sclerosis, which leads to the severe disintegration of the central white matter, on functional connectivity patterns in spontaneous cortical activity. Using a data driven approach based on the strength of a salient pattern of cognitive pathology, we identified distinct networks that exhibit increases in functional connectivity despite the presence of strong and diffuse reductions of the central white-matter integrity. The default mode network emerged as a core target of these connectivity modulations, showing enhanced functional coupling in bilateral inferior parietal cortex, posterior cingulate, and medial prefrontal cortex. These findings imply a complex and diverging relation of anatomical and functional connectivity in early multiple sclerosis and, thus, add an important observation for understanding how cognitive abilities and CNS integrity may be reflected in the intrinsic covariance of functional signals.

Noise alters beta-band activity in superior temporal cortex during audiovisual speech processing.

Speech recognition is improved when complementary visual information is available, especially under noisy acoustic conditions. Functional neuroimaging studies have suggested that the superior temporal sulcus (STS) plays an important role for this improvement. The spectrotemporal dynamics underlying audiovisual speech processing in the STS, and how these dynamics are affected by auditory noise, are not well understood. Using electroencephalography, we investigated how auditory noise affects audiovisual speech processing in event-related potentials (ERPs) and oscillatory activity. Spoken syllables were presented in audiovisual (AV) and auditory only (A) trials at three different auditory noise levels (no, low, and high). Responses to A stimuli were subtracted from responses to AV stimuli, separately for each noise level, and these responses were subjected to the statistical analysis. Central ERPs differed between the no noise and the two noise conditions from 130 to 150 ms and 170 to 210 ms after auditory stimulus onset. Source localization using the local autoregressive average procedure revealed an involvement of the lateral temporal lobe, encompassing the superior and middle temporal gyrus. Neuronal activity in the beta-band (16 to 32 Hz) was suppressed at central channels around 100 to 400 ms after auditory stimulus onset in the averaged AV minus A signal over the three noise levels. This suppression was smaller in the high noise compared to the no noise and low noise condition, possibly reflecting disturbed recognition or altered processing of multisensory speech stimuli. Source analysis of the beta-band effect using linear beamforming demonstrated an involvement of the STS. Our study shows that auditory noise alters audiovisual speech processing in ERPs localized to lateral temporal lobe and provides evidence that beta-band activity in the STS plays a role for audiovisual speech processing under regular and noisy acoustic conditions.

Functionally specific oscillatory activity correlates between visual and auditory cortex in the blind.

Many studies have shown that the visual cortex of blind humans is activated in non-visual tasks. However, the electrophysiological signals underlying this cross-modal plasticity are largely unknown. Here, we characterize the neuronal population activity in the visual and auditory cortex of congenitally blind humans and sighted controls in a complex cognitive task. We recorded magnetoencephalographic responses from participants performing semantic categorization of meaningful sounds that followed the presentation of a semantically related or unrelated haptic object. Source analysis of the spectrally resolved magnetoencephalography data revealed that: (i) neuronal responses to sounds were stronger and longer lasting in the auditory cortex of blind subjects; (ii) auditory stimulation elicited strong oscillatory responses in the visual cortex of blind subjects that closely resembled responses to visual stimulation in sighted humans; (iii) the signal in the gamma frequency range was modulated by semantic congruency between the sounds and the preceding haptic objects; and (iv) signal power in the gamma range was correlated on a trial-by-trial basis between auditory and visual cortex in blind subjects, and the strength of this correlation was modulated by semantic congruency. Our results suggest that specifically oscillatory activity in the gamma range reflects non-visual processing in the visual cortex of blind individuals. Moreover, our results provide evidence that the deprived visual cortex is functionally integrated into a larger network that serves non-visual functions.

Shortened Motor Evoked Potential Latency in the Epileptic Hemisphere of Children With Focal Epilepsy.

PURPOSE: Motor evoked potential (MEP) amplitude and latency are acquired routinely during neuronavigated transcranial magnetic stimulation, a method of functional mapping of the motor cortex before epilepsy surgery. Although MEP amplitude is routinely used to generate a motor map, MEP latency in patients with focal epilepsy has not been studied systematically. Given that epilepsy may alter myelination, we tested whether intrinsic hand muscle MEPs obtained from the hemisphere containing a seizure focus differ in latency from MEPs collected from the opposite hemisphere. METHODS: Latencies of abductor pollicis brevis MEPs were obtained during routine motor mapping by neuronavigated transcranial magnetic stimulation in children with intractable, unihemispheric focal epilepsy. The primary motor cortex was stimulated bilaterally in all cases. Only data from patients without a lesion involving the corticospinal tract were included. We tested whether abductor pollicis brevis MEP latency varied as a function of seizure focus lateralization. RESULTS: In the 17 patients who met the inclusion criteria, the mean latency of MEPs with amplitudes in the top and bottom quartiles was shorter in the epileptic hemisphere. Interhemispheric latency difference was greater in patients with lesional epilepsy than in those with nonlesional epilepsy (0.7 ± 0.4 vs. 0.1 ± 0.6 milliseconds, P = 0.02). CONCLUSIONS: Motor evoked potential latency was shortened in the epileptic hemisphere of children with focal epilepsy.

Functional connectivity signatures of NMDAR dysfunction in schizophrenia-integrating findings from imaging genetics and pharmaco-fMRI.

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS).

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits. RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports. CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations.

The saccadic spike artifact in MEG.

Electro- and magnetoencephalography (EEG/MEG) are the means to investigate the dynamics of neuronal activity non-invasively in the human brain. However, both EEG and MEG are also sensitive to non-neural sources, which can severely complicate the interpretation. The saccadic spike potential (SP) at saccade onset has been identified as a particularly problematic artifact in EEG because it closely resembles synchronous neuronal gamma band activity. While the SP and its confounding effects on EEG have been thoroughly characterized, the corresponding artifact in MEG, the saccadic spike field (SF), has not been investigated. Here we provide a detailed characterization of the SF. We simultaneously recorded MEG, EEG, gaze position and electrooculogram (EOG). We compared the SF in MEG for different saccade sizes and directions and contrasted it with the well-known SP in EEG. Our results reveal a saccade amplitude and direction dependent, lateralized saccadic spike artifact, which was most prominent in the gamma frequency range. The SF was strongest at frontal and temporal sensors but unlike the SP in EEG did not contaminate parietal sensors. Furthermore, we observed that the source configurations of the SF were comparable for regular and miniature saccades. Using distributed source analysis we identified the sources of the SF in the extraocular muscles. In summary, our results show that the SF in MEG closely resembles neuronal activity in frontal and temporal sensors. Our detailed characterization of the SF constitutes a solid basis for assessing possible saccadic spike related contamination in MEG experiments.

Oscillatory MEG gamma band activity dissociates perceptual and conceptual aspects of visual object processing: a combined repetition/conceptual priming study.

We used a combined repetition/conceptual priming task to investigate attenuations of induced gamma-band activity (iGBA) due to prior experience. We hypothesized that distinguishable iGBA suppression effects can be related to the processing of (a) perceptual aspects, and (b) conceptual aspects of cortical object representations. Participants were asked to perform a semantic classification task with pictures of real world objects and their semantically corresponding words, using a design that isolated distinct levels of the neural suppression effect. By means of volumetric source analysis we located stimulus domain-specific iGBA repetition suppression effects (60-90 Hz) in temporal, parietal, and occipital areas of the human cortex. In contrast, domain-unspecific iGBA repetition suppression, corresponding to conceptual priming, was restricted to left temporal brain regions. We propose that the selective involvement of left temporal areas points to the activation of conceptual representations, whereas more posterior temporal, parietal, and occipital areas probably reflect perceptual aspects of higher-order visual object processing.

Neural complexity is a common denominator of human consciousness across diverse regimes of cortical dynamics.

What is the common denominator of consciousness across divergent regimes of cortical dynamics? Does consciousness show itself in decibels or in bits? To address these questions, we introduce a testbed for evaluating electroencephalogram (EEG) biomarkers of consciousness using dissociations between neural oscillations and consciousness caused by rare genetic disorders. Children with Angelman syndrome (AS) exhibit sleep-like neural dynamics during wakefulness. Conversely, children with duplication 15q11.2-13.1 syndrome (Dup15q) exhibit wake-like neural dynamics during non-rapid eye movement (NREM) sleep. To identify highly generalizable biomarkers of consciousness, we trained regularized logistic regression classifiers on EEG data from wakefulness and NREM sleep in children with AS using both entropy measures of neural complexity and spectral (i.e., neural oscillatory) EEG features. For each set of features, we then validated these classifiers using EEG from neurotypical (NT) children and abnormal EEGs from children with Dup15q. Our results show that the classification performance of entropy-based EEG biomarkers of conscious state is not upper-bounded by that of spectral EEG features, which are outperformed by entropy features. Entropy-based biomarkers of consciousness may thus be highly adaptable and should be investigated further in situations where spectral EEG features have shown limited success, such as detecting covert consciousness or anesthesia awareness.

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome.

BACKGROUND: There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. METHODS: Basmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12-13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents. RESULTS: Basmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life. CONCLUSIONS: Basmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome. TRIAL REGISTRATION: The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

Resting state EEG power spectrum and functional connectivity in autism: a cross-sectional analysis.

BACKGROUND: Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed. METHODS: We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2-32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants' MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%-30% split). RESULTS: In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52-0.62, specificity 0.59-0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset. LIMITATIONS: The statistical power to detect weak effects-of the magnitude of those found in the training dataset-in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset's effects. CONCLUSIONS: This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects.