40 Hz Steady-State Response in Human Auditory Cortex Is Shaped by GABAergic Neuronal Inhibition.

The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, non-invasive physiological biomarker for schizophrenia and related neuropsychiatric disorders. The 40 Hz ASSR might be amplified by synaptic interactions in cortical circuits, which are, in turn, disturbed in neuropsychiatric disorders. Here, we tested whether the 40 Hz ASSR in human auditory cortex depends on two key synaptic components of neuronal interactions within cortical circuits: excitation via N-methyl-aspartate glutamate (NMDA) receptors and inhibition via gamma-amino-butyric acid (GABA) receptors. We combined magnetoencephalography (MEG) recordings with placebo-controlled, low-dose pharmacological interventions in the same healthy human participants (13 males, 7 females). All participants exhibited a robust 40 Hz ASSR in auditory cortices, especially in the right hemisphere, under placebo. The GABAA receptor-agonist lorazepam increased the amplitude of the 40 Hz ASSR, while no effect was detectable under the NMDA-blocker memantine. Our findings indicate that the 40 Hz ASSR in auditory cortex involves synaptic (and likely intracortical) inhibition via the GABA-A receptor, thus highlighting its utility as a mechanistic signature of cortical circuit dysfunctions involving GABAergic inhibition.Significance statement The 40 Hz auditory steady-state response is a candidate non-invasive biomarker for schizophrenia and related neuropsychiatric disorders. Yet, the understanding of the synaptic basis of this neurophysiological signature in humans has remained incomplete. We combined magnetoencephalography (MEG) recordings with placebo-controlled pharmacological interventions in healthy human subjects to test the modulation of the 40 Hz ASSR in auditory cortex by two synaptic components that have been implicated in the generation of neuronal oscillations in cortical microcircuits: glutamate N-methyl-aspartate glutamate (NMDA) receptors and gamma-amino-butyric acid (GABA) -A receptors. Boosting GABAergic transmission, but not blocking NMDA-receptors, increased the amplitude of this ASSR. Thus, GABAergic inhibition modulates 40 Hz steady-state responses in auditory cortex.

Increased neural variability in adolescents with ADHD symptomatology: Evidence from a single-trial EEG study.

Increased intrasubject variability of reaction time (RT) refers to inconsistency in an individual's speed of responding to a task. This increased variability has been suggested as a fundamental feature of attention deficit hyperactivity disorder (ADHD), however, its neural sources are still unclear. In this study, we aimed to examine whether such inconsistency at the behavioral level would be accompanied by inconsistency at the neural level; and whether different types of neural and behavioral variability would be related to ADHD symptomatology. We recorded electroencephalogram (EEG) data from 62 adolescents, who were part of a prospective longitudinal study on the development of ADHD. We examined trial-by-trial neural variability in response to visual stimuli in two cognitive tasks. Adolescents with high ADHD symptomatology exhibited an increased neural variability before the presentation of the stimulus, but when presented with a visual stimulus, this variability decreased to a level that was similar to that exhibited by participants with low ADHD symptomatology. In contrast with our prediction, neural variability was unrelated to the magnitude of behavioral variability. Our findings suggest that adolescents with higher symptoms are characterized by increased neural variability before the stimulation, which might reflect a difficulty in alertness to the forthcoming stimulus; but this increased neural variability does not seem to account for their RT variability.

Ustekinumab during pregnancy in patients with inflammatory bowel disease: a prospective multicentre cohort study.

BACKGROUND: Women with inflammatory bowel diseases (IBD) often receive biologics to maintain remission during pregnancy. AIMS: To assess maternal and neonatal outcomes in patients with IBD treated with ustekinumab (UST) during pregnancy METHODS: In a multicentre, prospective cohort study, we recruited women with IBD treated with UST during pregnancy between 2019 and 2021. Outcomes were compared among patients treated with UST, anti-tumour necrosis factor α, (anti-TNF) and non-UST, non-anti-TNF therapies. UST-treated patients were matched 1:2 to controls according to age, body mass index and parity. Newborns were followed up to 12 months. RESULTS: We recruited 129 pregnant patients: UST 27; anti-TNF 52; non-UST, non-anti-TNF 50 (thiopurine or mesalazine 30, no therapy 20); Crohn's disease 25 (96.9%). Overall, pregnancy, neonatal and newborn outcomes were satisfactory, with no significant differences among patients treated with UST, anti-TNF and non-UST non-anti-TNF agents for obstetrical maternal complications [UST 3 (11.5%), anti TNF 12 (23.1%), non UST, non-anti-TNF 4 (8.2%), p = 0.095], pre-term delivery [1 (4.3%), 9 (18.4%), 4 (5.7%), p = 0.133], low birth weight [1 (4.2%), 5 (10.2%), 4 (8.3%), p = 0.679], or first year newborn hospitalisation [2 (9.1%), 4 (8.2%), 3 (6.1%), p = 0.885]. CONCLUSION: Pregnant patients with IBD treated with UST demonstrated favourable pregnancy and neonatal outcomes that were comparable with those in patients treated with anti-TNF or other therapy. Data are reassuring for patients with IBD and their physicians when considering UST during pregnancy.

Home-quarantine during the initial Covid-19 outbreak in Israel: parent perceived impact on children with ASD.

Background: Studies have reported that Covid-19 home-quarantine periods have had mostly negative psychological impact on children with ASD and their families. Here we examined parent perceived impact of a 6-week quarantine period imposed in Israel at the beginning of the Covid-19 outbreak, in mid-March 2020. Methods: An anonymous online questionnaire was completed by parents of 268 children with ASD. Parents rated deterioration/improvement in their child's behaviors, abilities, mood, sleep, and anxiety along with changes in their own mood, sleep, parenting skills, and family relationships. We performed t-tests and ANOVA analyses to assess the significance of perceived impact on each domain and potential differences in the impact across families with children of different ages, genders, and levels of required support as well as families that experienced different magnitudes of economic hardships. Results: Parents reported significant deterioration in their mood and sleep along with significant improvements in relationships with their spouse and child with ASD, and in their parenting skills. Parents also reported significant increases in the severity of tantrums, anxiety, and restricted and repetitive behavior symptoms along with significant improvements in social and communication abilities of their child with ASD. Ratings were significantly lower in families of ASD children who regularly require more support and in families that experienced economic hardships. Conclusions: While periods of home-quarantine create numerous hardships for families of children with ASD, they may also offer an opportunity for improving parenting skills, family relationships, and children's social communication abilities with potential relevance for improving remote services.

Altered slow-wave sleep activity in children with rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation syndrome.

STUDY OBJECTIVES: Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare condition. Little is known about sleep/wake and slow-wave activity in this condition, although the central hypothalamic dysfunction associated with autonomic dysregulation would make the occurrence of SWA deregulation most likely. METHODS: Two children with clinical presentation of ROHHAD syndrome were evaluated, diagnosed, and treated. Their polysomnographic studies were compared with 4 matched children with obstructive sleep apnea and 6 controls. RESULTS: Children that were clinically diagnosed with ROHHAD exhibited significantly weaker slow-wave activity power and shallower slow-wave activity slopes during the first 2 sleep cycles compared with children with obstructive sleep apnea or controls. CONCLUSIONS: This study shows that children with ROHHAD have suppressed slow-wave activity, possibly because of hypothalamic dysregulation that may contribute to their rapid-onset obesity and excessive daytime sleepiness.

Reduced sleep pressure in young children with autism.

STUDY OBJECTIVES: Sleep disturbances and insomnia are highly prevalent in children with Autism Spectrum Disorder (ASD). Sleep homeostasis, a fundamental mechanism of sleep regulation that generates pressure to sleep as a function of wakefulness, has not been studied in children with ASD so far, and its potential contribution to their sleep disturbances remains unknown. Here, we examined whether slow-wave activity (SWA), a measure that is indicative of sleep pressure, differs in children with ASD. METHODS: In this case-control study, we compared overnight electroencephalogram (EEG) recordings that were performed during Polysomnography (PSG) evaluations of 29 children with ASD and 23 typically developing children. RESULTS: Children with ASD exhibited significantly weaker SWA power, shallower SWA slopes, and a decreased proportion of slow-wave sleep in comparison to controls. This difference was largest during the first 2 hours following sleep onset and decreased gradually thereafter. Furthermore, SWA power of children with ASD was significantly negatively correlated with the time of their sleep onset in the lab and at home, as reported by parents. CONCLUSIONS: These results suggest that children with ASD may have a dysregulation of sleep homeostasis that is manifested in reduced sleep pressure. The extent of this dysregulation in individual children was apparent in the amplitude of their SWA power, which was indicative of the severity of their individual sleep disturbances. We, therefore, suggest that disrupted homeostatic sleep regulation may contribute to sleep disturbances in children with ASD.

The Relationship between Trial-by-Trial Variability and Oscillations of Cortical Population Activity.

Neural activity fluctuates over time, creating considerable variability across trials. This trial-by-trial neural variability is dramatically reduced ("quenched") after the presentation of sensory stimuli. Likewise, the power of neural oscillations, primarily in the alpha-beta band, is also reduced after stimulus onset. Despite their similarity, these phenomena have so far been studied and discussed independently. We hypothesized that the two phenomena are tightly coupled in electrophysiological recordings of large cortical neural populations. To test this, we examined magnetoencephalography (MEG) recordings of healthy subjects viewing repeated presentations of a visual stimulus. The timing, amplitude, and spatial topography of variability-quenching and power-suppression were remarkably similar. Neural variability quenching was eliminated by excluding the alpha-beta band from the recordings, but not by excluding other frequency-bands. Moreover, individual magnitudes of alpha-beta band-power explained 86% of between-subject differences in variability quenching. An alternative mechanism that may generate variability quenching is increased phase alignment across trials. However, changes in inter-trial-phase-coherence (ITPC) exhibited distinct timing and no correlations with the magnitude of variability quenching in individual participants. These results reveal that neural variability quenching is tightly coupled with stimulus-induced changes in the power of alpha-beta band oscillations, associating two phenomena that have so far been studied in isolation.

Neural Variability Is Quenched by Attention.

Attention can be subdivided into several components, including alertness and spatial attention. It is believed that the behavioral benefits of attention, such as increased accuracy and faster reaction times, are generated by an increase in neural activity and a decrease in neural variability, which enhance the signal-to-noise ratio of task-relevant neural populations. However, empirical evidence regarding attention-related changes in neural variability in humans is extremely rare. Here we used EEG to demonstrate that trial-by-trial neural variability was reduced by visual cues that modulated alertness and spatial attention. Reductions in neural variability were specific to the visual system and larger in the contralateral hemisphere of the attended visual field. Subjects with higher initial levels of neural variability and larger decreases in variability exhibited greater behavioral benefits from attentional cues. These findings demonstrate that both alertness and spatial attention modulate neural variability and highlight the importance of reducing/quenching neural variability for attaining the behavioral benefits of attention.SIGNIFICANCE STATEMENT Attention is thought to improve perception by increasing the signal-to-noise ratio of the neuronal populations that encode the attended stimulus. Signal-to-noise ratio can be enhanced by increasing neural response (signal) and/or by reducing neural variability (noise). The ability of attention to increase neural responses has been studied extensively, but the effects of attention on neural variability have rarely been examined in humans. Here, we demonstrate that modulating different components of attention, including alertness and spatial attention, reduces neural variability in humans. Furthermore, we show that subjects with larger reductions in neural variability exhibit greater behavioral benefits from attention. These results demonstrate that reduction of neural variability is a fundamental feature of attentional processes in humans with clear behavioral importance.

The Magnitude of Trial-By-Trial Neural Variability Is Reproducible over Time and across Tasks in Humans.

Numerous studies have shown that neural activity in sensory cortices is remarkably variable over time and across trials even when subjects are presented with an identical repeating stimulus or task. This trial-by-trial neural variability is relatively large in the prestimulus period and considerably smaller (quenched) following stimulus presentation. Previous studies have suggested that the magnitude of neural variability affects behavior such that perceptual performance is better on trials and in individuals where variability quenching is larger. To what degree are neural variability magnitudes of individual subjects flexible or static? Here, we used EEG recordings from adult humans to demonstrate that neural variability magnitudes in visual cortex are remarkably consistent across different tasks and recording sessions. While magnitudes of neural variability differed dramatically across individual subjects, they were surprisingly stable across four tasks with different stimuli, temporal structures, and attentional/cognitive demands as well as across experimental sessions separated by one year. These experiments reveal that, in adults, neural variability magnitudes are mostly solidified individual characteristics that change little with task or time, and are likely to predispose individual subjects to exhibit distinct behavioral capabilities.

Neural Variability Quenching Predicts Individual Perceptual Abilities.

Neural activity during repeated presentations of a sensory stimulus exhibits considerable trial-by-trial variability. Previous studies have reported that trial-by-trial neural variability is reduced (quenched) by the presentation of a stimulus. However, the functional significance and behavioral relevance of variability quenching and the potential physiological mechanisms that may drive it have been studied only rarely. Here, we recorded neural activity with EEG as subjects performed a two-interval forced-choice contrast discrimination task. Trial-by-trial neural variability was quenched by ∼40% after the presentation of the stimulus relative to the variability apparent before stimulus presentation, yet there were large differences in the magnitude of variability quenching across subjects. Individual magnitudes of quenching predicted individual discrimination capabilities such that subjects who exhibited larger quenching had smaller contrast discrimination thresholds and steeper psychometric function slopes. Furthermore, the magnitude of variability quenching was strongly correlated with a reduction in broadband EEG power after stimulus presentation. Our results suggest that neural variability quenching is achieved by reducing the amplitude of broadband neural oscillations after sensory input, which yields relatively more reproducible cortical activity across trials and enables superior perceptual abilities in individuals who quench more. SIGNIFICANCE STATEMENT: Variability quenching is a phenomenon in which neural variability across trials is reduced by the presentation of a stimulus. Although this phenomenon has been reported across a variety of animal and human studies, its functional significance and behavioral relevance have been examined only rarely. Here, we report novel empirical evidence from humans revealing that variability quenching differs dramatically across individual subjects and explains to a certain degree why some individuals exhibit better perceptual abilities than others. In addition, we found a strong relationship between variability quenching and suppression of broadband neural oscillations. Together, our results reveal the importance of reproducible cortical activity for enabling better perceptual abilities and suggest a potential underlying mechanism that may explain why variability quenching occurs.

Increased ongoing neural variability in ADHD.

Attention Deficit Hyperactivity Disorder (ADHD) has been described as a disorder where frequent lapses of attention impair the ability of an individual to focus/attend in a sustained manner, thereby generating abnormally large intra-individual behavioral variability across trials. Indeed, increased reaction time (RT) variability is a fundamental behavioral characteristic of individuals with ADHD found across a large number of cognitive tasks. But what is the underlying neurophysiology that might generate such behavioral instability? Here, we examined trial-by-trial EEG response variability to visual and auditory stimuli while subjects' attention was diverted to an unrelated task at the fixation cross. Comparisons between adult ADHD and control participants revealed that neural response variability was significantly larger in the ADHD group as compared with the control group in both sensory modalities. Importantly, larger trial-by-trial variability in ADHD was apparent before and after stimulus presentation as well as in trials where the stimulus was omitted, suggesting that ongoing (rather than stimulus-evoked) neural activity is continuously more variable (noisier) in ADHD. While the patho-physiological mechanisms causing this increased neural variability remain unknown, they appear to act continuously rather than being tied to a specific sensory or cognitive process.