Distinct lateral hypothalamic CaMKIIα neuronal populations regulate wakefulness and locomotor activity.

For nearly a century, evidence has accumulated indicating that the lateral hypothalamus (LH) contains neurons essential to sustain wakefulness. While lesion or inactivation of LH neurons produces a profound increase in sleep, stimulation of inhibitory LH neurons promotes wakefulness. To date, the primary wake-promoting cells that have been identified in the LH are the hypocretin/orexin (Hcrt) neurons, yet these neurons have little impact on total sleep or wake duration across the 24-h period. Recently, we and others have identified other LH populations that increase wakefulness. In the present study, we conducted microendoscopic calcium imaging in the LH concomitant with EEG and locomotor activity (LMA) recordings and found that a subset of LH neurons that express Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) are preferentially active during wakefulness. Chemogenetic activation of these neurons induced sustained wakefulness and greatly increased LMA even in the absence of Hcrt signaling. Few LH CaMKIIα-expressing neurons are hypocretinergic or histaminergic while a small but significant proportion are GABAergic. Ablation of LH inhibitory neurons followed by activation of the remaining LH CaMKIIα neurons induced similar levels of wakefulness but blunted the LMA increase. Ablated animals showed no significant changes in sleep architecture but both spontaneous LMA and high theta (8 to 10 Hz) power during wakefulness were reduced. Together, these findings indicate the existence of two subpopulations of LH CaMKIIα neurons: an inhibitory population that promotes locomotion without affecting sleep architecture and an excitatory population that promotes prolonged wakefulness even in the absence of Hcrt signaling.

Separate Cue- and Alpha-Related Mechanisms for Distractor Suppression.

Research on selective attention has largely focused on the enhancement of behaviorally important information, with less focus on the suppression of distracting information. Enhancement and suppression can operate through a push-pull relationship attributable to competitive interactions among neural populations. There has been considerable debate, however, regarding (1) whether suppression can be voluntarily deployed, independent of enhancement, and (2) whether voluntary deployment of suppression is associated with neural processes occurring prior to the distractor onset. Here, we investigated the interplay between pre- and post-distractor neural processes, while male and female human subjects performed a visual search task with a cue that indicated the location of an upcoming distractor. We utilized two established EEG markers of suppression: the distractor positivity (PD) and alpha power (∼8-15 Hz). The PD-a component of event-related potentials-has been linked with successful distractor suppression, and increased alpha power has been linked with attenuated sensory processing. Cueing the location of an upcoming distractor speeded responses and led to an earlier PD, consistent with earlier suppression due to strategic use of a spatial cue. In comparison, higher predistractor alpha power contralateral to distractors led to a later PD, consistent with later suppression. Lower alpha power contralateral to distractors instead led to distractor-related attentional capture. Lateralization of alpha power was not linked to the spatial cue. This observation, combined with differences in the timing of suppression-as indexed by earlier and later PD components-demonstrates that cue-related, voluntary suppression can occur separate from alpha-related gating of sensory processing.

EEG microstates analysis after TMS in patients with subacute stroke during the resting state.

To investigate whether intermittent theta burst stimulation over the cerebellum induces changes in resting-state electroencephalography microstates in patients with subacute stroke and its correlation with cognitive and emotional function. Twenty-four stroke patients and 17 healthy controls were included in this study. Patients and healthy controls were assessed at baseline, including resting-state electroencephalography and neuropsychological scales. Fifteen patients received lateral cerebellar intermittent theta burst stimulation as well as routine rehabilitation training (intermittent theta burst stimulation-RRT group), whereas 9 patients received only conventional rehabilitation training (routine rehabilitation training group). After 2 wk, baseline data were recorded again in both groups. Stroke patients exhibited reduced parameters in microstate D and increased parameters in microstate C compared with healthy controls. However, after the administration of intermittent theta burst stimulation over the lateral cerebellum, significant alterations were observed in the majority of metrics for both microstates D and C. Lateral cerebellar intermittent theta burst stimulation combined with conventional rehabilitation has a stronger tendency to improve emotional and cognitive function in patients with subacute stroke than conventional rehabilitation. The improvement of mood and cognitive function was significantly associated with microstates C and D. We identified electroencephalography microstate spatiotemporal dynamics associated with clinical improvement following a course of intermittent theta burst stimulation therapy.

Enhancing specialization of attention-related EEG power and phase synchronism brain patterns by meditation.

Meditation, mental training that aims to improve one's ability to regulate their cognition, has been widely applied in clinical medicine. However, the mechanism by which meditation affects brain activity is still unclear. To explore this question, electroencephalogram data were recorded in 20 long-term meditators and 20 nonmeditators during 2 high-level cognitive tasks (meditation and mental calculation) and a relaxed resting state (control). Then, the power spectral density and phase synchronization of the electroencephalogram were extracted and compared between these 2 groups. In addition, machine learning was used to discriminate the states within each group. We found that the meditation group showed significantly higher classification accuracy and calculation efficiency than the control group. Then, during the calculation task, both the power and global phase synchronism of the gamma response decreased in meditators compared to their relaxation state; yet, no such change was observed in the control group. A potential explanation for our observations is that meditation improved the flexibility of the brain through neural plastic mechanism. In conclusion, we provided robust evidence that long-term meditation experience could produce detectable neurophysiological changes in brain activity, which possibly enhance the functional segregation and/or specialization in the brain.

Divergent electroencephalogram resting-state functional network alterations in subgroups of autism spectrum disorder: a symptom-based clustering analysis.

Autism spectrum disorder (ASD) is characterized by etiological and phenotypic heterogeneity. Despite efforts to categorize ASD into subtypes, research on specific functional connectivity changes within ASD subgroups based on clinical presentations is limited. This study proposed a symptom-based clustering approach to identify subgroups of ASD based on multiple clinical rating scales and investigate their distinct Electroencephalogram (EEG) functional connectivity patterns. Eyes-opened resting-state EEG data were collected from 72 children with ASD and 63 typically developing (TD) children. A data-driven clustering approach based on Social Responsiveness Scales-Second Edition and Vinland-3 scores was used to identify subgroups. EEG functional connectivity and topological characteristics in four frequency bands were assessed. Two subgroups were identified: mild ASD (mASD, n = 37) and severe ASD (sASD, n = 35). Compared to TD, mASD showed increased functional connectivity in the beta band, while sASD exhibited decreased connectivity in the alpha band. Significant between-group differences in global and regional topological abnormalities were found in both alpha and beta bands. The proposed symptom-based clustering approach revealed the divergent functional connectivity patterns in the ASD subgroups that was not observed in typical ASD studies. Our study thus provides a new perspective to address the heterogeneity in ASD research.

Assessment of the excitation-inhibition ratio in the Fmr1 KO2 mouse using neuronal oscillation dynamics.

In vitro and ex vivo studies have shown consistent indications of hyperexcitability in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mouse model of autism spectrum disorder. We recently introduced a method to quantify network-level functional excitation-inhibition ratio from the neuronal oscillations. Here, we used this measure to study whether the implicated synaptic excitation-inhibition disturbances translate to disturbances in network physiology in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1) gene knockout model. Vigilance-state scoring was used to extract segments of inactive wakefulness as an equivalent behavioral condition to the human resting-state and, subsequently, we performed high-frequency resolution analysis of the functional excitation-inhibition biomarker, long-range temporal correlations, and spectral power. We corroborated earlier studies showing increased high-frequency power in Fragile X Messenger Ribonucleoprotein 1 (Fmr1) knockout mice. Long-range temporal correlations were higher in the gamma frequency ranges. Contrary to expectations, functional excitation-inhibition was lower in the knockout mice in high frequency ranges, suggesting more inhibition-dominated networks. Exposure to the Gamma-aminobutyric acid (GABA)-agonist clonazepam decreased the functional excitation-inhibition in both genotypes, confirming that increasing inhibitory tone results in a reduction of functional excitation-inhibition. In addition, clonazepam decreased electroencephalogram power and increased long-range temporal correlations in both genotypes. These findings show applicability of these new resting-state electroencephalogram biomarkers to animal for translational studies and allow investigation of the effects of lower-level disturbances in excitation-inhibition balance.

Neural response properties predict perceived contents and locations elicited by intracranial electrical stimulation of human auditory cortex.

Intracranial electrical stimulation (iES) of auditory cortex can elicit sound experiences with a variety of perceived contents (hallucination or illusion) and locations (contralateral or bilateral side), independent of actual acoustic inputs. However, the neural mechanisms underlying this elicitation heterogeneity remain undiscovered. Here, we collected subjective reports following iES at 3062 intracranial sites in 28 patients (both sexes) and identified 113 auditory cortical sites with iES-elicited sound experiences. We then decomposed the sound-induced intracranial electroencephalogram (iEEG) signals recorded from all 113 sites into time-frequency features. We found that the iES-elicited perceived contents can be predicted by the early high-γ features extracted from sound-induced iEEG. In contrast, the perceived locations elicited by stimulating hallucination sites and illusion sites are determined by the late high-γ and long-lasting α features, respectively. Our study unveils the crucial neural signatures of iES-elicited sound experiences in human and presents a new strategy to hearing restoration for individuals suffering from deafness.

What Does the Human Olfactory System Do, and How Does It Do It?

Historically, the human sense of smell has been regarded as the odd stepchild of the senses, especially compared to the sensory bravado of seeing, touching, and hearing. The idea that the human olfaction has little to contribute to our experience of the world is commonplace, though with the emergence of COVID-19 there has rather been a sea change in this understanding. An ever increasing body of work has convincingly highlighted the keen capabilities of the human nose and the sophistication of the human olfactory system. Here, we provide a concise overview of the neuroscience of human olfaction spanning the last 10-15 years, with focus on the peripheral and central mechanisms that underlie how odor information is processed, packaged, parceled, predicted, and perturbed to serve odor-guided behaviors. We conclude by offering some guideposts for harnessing the next decade of olfactory research in all its shapes and forms.

Rapid Processing of Invisible Fearful Faces in the Human Amygdala.

Rapid detection of a threat or its symbol (e.g., fearful face), whether visible or invisible, is critical for human survival. This function is suggested to be enabled by a subcortical pathway to the amygdala independent of the cortex. However, conclusive electrophysiological evidence in humans is scarce. Here, we explored whether the amygdala can rapidly encode invisible fearful faces. We recorded intracranial electroencephalogram (iEEG) responses in the human (both sexes) amygdala to faces with fearful, happy, and neutral emotions rendered invisible by backward masking. We found that a short-latency intracranial event-related potential (iERP) in the amygdala, beginning 88 ms poststimulus onset, was preferentially evoked by invisible fearful faces relative to invisible happy or neutral faces. The rapid iERP exhibited selectivity to the low spatial frequency (LSF) component of the fearful faces. Time-frequency iEEG analyses further identified a rapid amygdala response preferentially for LSF fearful faces at the low gamma frequency band, beginning 45 ms poststimulus onset. In contrast, these rapid responses to invisible fearful faces were absent in cortical regions, including early visual areas, the fusiform gyrus, and the parahippocampal gyrus. These findings provide direct evidence for the existence of a subcortical pathway specific for rapid fear detection in the amygdala and demonstrate that the subcortical pathway can function without conscious awareness and under minimal influence from cortical areas.SIGNIFICANCE STATEMENT Automatic detection of biologically relevant stimuli, such as threats or dangers, has remarkable survival value. Here, we provide direct intracranial electrophysiological evidence that the human amygdala preferentially responds to fearful faces at a rapid speed, despite the faces being invisible. This rapid, fear-selective response is restricted to faces containing low spatial frequency information transmitted by magnocellular neurons and does not appear in cortical regions. These results support the existence of a rapid subcortical pathway independent of cortical pathways to the human amygdala.

Human brain imaging with high-density electroencephalography: Techniques and applications.

Electroencephalography (EEG) is a technique for non-invasively measuring neuronal activity in the human brain using electrodes placed on the participant's scalp. With the advancement of digital technologies, EEG analysis has evolved over time from the qualitative analysis of amplitude and frequency modulations to a comprehensive analysis of the complex spatiotemporal characteristics of the recorded signals. EEG is now considered a powerful tool for measuring neural processes in the same time frame in which they happen (i.e. the subsecond range). However, it is commonly argued that EEG suffers from low spatial resolution, which makes it difficult to localize the generators of EEG activity accurately and reliably. Today, the availability of high-density EEG (hdEEG) systems, combined with methods for incorporating information on head anatomy and sophisticated source-localization algorithms, has transformed EEG into an important neuroimaging tool. hdEEG offers researchers and clinicians a rich and varied range of applications. It can be used not only for investigating neural correlates in motor and cognitive neuroscience experiments, but also for clinical diagnosis, particularly in the detection of epilepsy and the characterization of neural impairments in a wide range of neurological disorders. Notably, the integration of hdEEG systems with other physiological recordings, such as kinematic and/or electromyography data, might be especially beneficial to better understand the neuromuscular mechanisms associated with deconditioning in ageing and neuromotor disorders, by mapping the neurokinematic and neuromuscular connectivity patterns directly in the brain.

How mind wandering influences motor control: The modulating role of movement difficulty.

It has been found that mind wandering can impair motor control. However, it remains unclear whether the impact of mind wandering on motor control is modulated by movement difficulty and its associated neural mechanisms. To address this issue, we manipulated movement difficulty using handedness and finger dexterity separately in two signal-response tasks with identical experiment designs, in which right-handed participants performed key-pressing and key-releasing movements with the specified fingers, and they had to intermittently report whether their attention was "On task" or "Off task." Key-releasing with the right index finger (RI) had a faster reaction time and stronger contralateral delta-theta (1-7 Hz) functional connectivity than with the left index (LI) in Experiment 1, and mind wandering only reduced the contralateral delta-theta functional connectivity and midfrontal delta-theta activity for key-releasing with RI. Key-pressing with right index and middle fingers (RIR) had a faster reaction time and stronger midfrontal delta-theta activity than with right index and ring fingers (RIR) in Experiment 2, and mind wandering only reduced the midfrontal delta-theta activity for key-pressing with RIM. Theta oscillations are vital in motor control. These findings suggest that mind wandering only impairs the motor control of relatively simple movements without affecting the difficult ones. It supports the notion that mind wandering competes for executive resources with the primary task. Moreover, the quantity of executive resources recruited for a task and how these resources are allocated is contingent upon the task difficulty, which may determine whether mind wandering would interfere with motor control.

Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation.

Cortical electroencephalograms (EEGs) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/f) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than excitation/inhibition ratio may alter EEG parameters. Thus, to test the robustness of the aperiodic exponent as a predictor of excitation/inhibition ratio, we analyzed video-EEG during active exploration in mice of both sexes during various pharmacological manipulations with the fitting oscillations and one over f (FOOOF) algorithm. We found that GABAA receptor (GABAAR)-positive allosteric modulators increased the aperiodic exponent, consistent with the hypothesis that an increased exponent signals enhanced cortical inhibition, but other drugs (ketamine and GABAAR antagonists at subconvulsive doses) did not follow the prediction. To tilt excitation/inhibition ratio more selectively toward excitation, we suppressed the activity of parvalbumin-positive interneurons with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Contrary to our expectations, circuit disinhibition with the DREADD increased the aperiodic exponent. We conclude that the aperiodic exponent of EEG power spectra does not yield a universally reliable marker of cortical excitation/inhibition ratio.NEW & NOTEWORTHY Neuropsychiatric illness may be associated with altered excitation/inhibition balance. A single electroencephalogram (EEG) parameter, the aperiodic exponent of power spectra, may predict the ratio between excitation and inhibition. Here, we use cortical EEGs in mice to evaluate this hypothesis, using pharmacological manipulations of known mechanism. We show that the aperiodic exponent of EEG power spectra is not a reliable marker of excitation/inhibition ratio. Thus, alternative markers of this ratio must be sought.

Dissociations between spontaneous electroencephalographic features and the perturbational complexity index in the minimally conscious state.

The analysis of spontaneous electroencephalogram (EEG) is a cornerstone in the assessment of patients with disorders of consciousness (DoC). Although preserved EEG patterns are highly suggestive of consciousness even in unresponsive patients, moderately or severely abnormal patterns are difficult to interpret. Indeed, growing evidence shows that consciousness can be present despite either large delta or reduced alpha activity in spontaneous EEG. Quantifying the complexity of EEG responses to direct cortical perturbations (perturbational complexity index [PCI]) may complement the observational approach and provide a reliable assessment of consciousness even when spontaneous EEG features are inconclusive. To seek empirical evidence of this hypothesis, we compared PCI with EEG spectral measures in the same population of minimally conscious state (MCS) patients (n = 40) hospitalized in rehabilitation facilities. We found a remarkable variability in spontaneous EEG features across MCS patients as compared with healthy controls: in particular, a pattern of predominant delta and highly reduced alpha power-more often observed in vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients-was found in a non-negligible number of MCS patients. Conversely, PCI values invariably fell above an externally validated empirical cutoff for consciousness in all MCS patients, consistent with the presence of clearly discernible, albeit fleeting, behavioural signs of awareness. These results confirm that, in some MCS patients, spontaneous EEG rhythms may be inconclusive about the actual capacity for consciousness and suggest that a perturbational approach can effectively compensate for this pitfall with practical implications for the individual patient's stratification and tailored rehabilitation.

Multiplex dynamic networks in the newborn brain disclose latent links with neurobehavioral phenotypes.

The higher brain functions arise from coordinated neural activity between distinct brain regions, but the spatial, temporal, and spectral complexity of these functional connectivity networks (FCNs) has challenged the identification of correlates with neurobehavioral phenotypes. Characterizing behavioral correlates of early life FCNs is important to understand the activity dependent emergence of neurodevelopmental performance and for improving health outcomes. Here, we develop an analysis pipeline for identifying multiplex dynamic FCNs that combine spectral and spatiotemporal characteristics of the newborn cortical activity. This data-driven approach automatically uncovers latent networks that show robust neurobehavioral correlations and consistent effects by in utero drug exposure. Altogether, the proposed pipeline provides a robust end-to-end solution for an objective assessment and quantitation of neurobehaviorally meaningful network constellations in the highly dynamic cortical functions.

Evoked oscillatory cortical activity during acute pain: Probing brain in pain by transcranial magnetic stimulation combined with electroencephalogram.

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (acute pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, ß1, and ß2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all p < .05). The remote (parietal-occipital) decrease in α-band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α-band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased ß1-band power locally compared with non-noxious warm (p = .015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and ß band oscillations and may have relevance for pain therapies.

EEG decoding with spatiotemporal convolutional neural network for visualization and closed-loop control of sensorimotor activities: A simultaneous EEG-fMRI study.

Closed-loop neurofeedback training utilizes neural signals such as scalp electroencephalograms (EEG) to manipulate specific neural activities and the associated behavioral performance. A spatiotemporal filter for high-density whole-head scalp EEG using a convolutional neural network can overcome the ambiguity of the signaling source because each EEG signal includes information on the remote regions. We simultaneously acquired EEG and functional magnetic resonance images in humans during the brain-computer interface (BCI) based neurofeedback training and compared the reconstructed and modeled hemodynamic responses of the sensorimotor network. Filters constructed with a convolutional neural network captured activities in the targeted network with spatial precision and specificity superior to those of the EEG signals preprocessed with standard pipelines used in BCI-based neurofeedback paradigms. The middle layers of the trained model were examined to characterize the neuronal oscillatory features that contributed to the reconstruction. Analysis of the layers for spatial convolution revealed the contribution of distributed cortical circuitries to reconstruction, including the frontoparietal and sensorimotor areas, and those of temporal convolution layers that successfully reconstructed the hemodynamic response function. Employing a spatiotemporal filter and leveraging the electrophysiological signatures of the sensorimotor excitability identified in our middle layer analysis would contribute to the development of a further effective neurofeedback intervention.

The effects of stress on reward responsiveness: a systematic review and preliminary meta-analysis of the event-related potential literature.

Exposure to stressful events is associated with a range of negative physical and mental health outcomes, including depression. It is critical to understand the mechanisms through which stress impacts mental health to identify promising targets for prevention and intervention efforts. Low-reward responsiveness is thought to be a mechanism of effects of stress on negative health outcomes and can be reliably measured at the neurophysiological level by using event-related potentials (ERPs), such as the reward positivity (RewP) component. The goal of this systematic review and preliminary meta-analysis was to examine evidence of associations between stress and alterations in reward responsiveness measured using ERPs. Through a systematic review of the literature, 23 studies examining the effects of laboratory-induced stressors and naturalistic stressors or perceived stress on reward responsiveness met study criteria, 13 of which were included in the meta-analysis. Most studies were conducted in undergraduate and community samples, with three selected for specific conditions, and primarily in adults. The systematic review supported evidence of associations between laboratory-induced stressors and blunted reward responsiveness as measured by the RewP but there were more mixed results when considering direct associations between naturalistic stressors/perceived stress and reward-related ERPs. Given that all studies examined the RewP, the meta-analysis focused on this component and indicated that there was a weak, nonsignificant negative association between stress and RewP. Results emphasize the complex nature of relations between stress and reward-related ERPs and the need to consider alternative models in future research. We also provide reporting recommendations for ERP researchers to facilitate future meta-analyses.

Sleep alterations as a function of 88 health indicators.

BACKGROUND: Alterations in sleep have been described in multiple health conditions and as a function of several medication effects. However, evidence generally stems from small univariate studies. Here, we apply a large-sample, data-driven approach to investigate patterns between in sleep macrostructure, quantitative sleep EEG, and health. METHODS: We use data from the MrOS Sleep Study, containing polysomnography and health data from a large sample (N = 3086) of elderly American men to establish associations between sleep macrostructure, the spectral composition of the electroencephalogram, 38 medical disorders, 2 health behaviors, and the use of 48 medications. RESULTS: Of sleep macrostructure variables, increased REM latency and reduced REM duration were the most common findings across health indicators, along with increased sleep latency and reduced sleep efficiency. We found that the majority of health indicators were not associated with objective EEG power spectral density (PSD) alterations. Associations with the rest were highly stereotypical, with two principal components accounting for 85-95% of the PSD-health association. PC1 consists of a decrease of slow and an increase of fast PSD components, mainly in NREM. This pattern was most strongly associated with depression/SSRI medication use and age-related disorders. PC2 consists of changes in mid-frequency activity. Increased mid-frequency activity was associated with benzodiazepine use, while decreases were associated with cardiovascular problems and associated medications, in line with a recently proposed hypothesis of immune-mediated circadian demodulation in these disorders. Specific increases in sleep spindle frequency activity were associated with taking benzodiazepines and zolpidem. Sensitivity analyses supported the presence of both disorder and medication effects. CONCLUSIONS: Sleep alterations are present in various health conditions.

Identifying conceptual neural responses to symbolic numerals.

The goal of measuring conceptual processing in numerical cognition is distanced by the possibility that neural responses to symbolic numerals are influenced by physical stimulus confounds. Here, we targeted conceptual responses to parity (even versus odd), using electroencephalogram (EEG) frequency-tagging with a symmetry/asymmetry design. Arabic numerals (2-9) were presented at 7.5 Hz in 50 s sequences; odd and even numbers were alternated to target differential, 'asymmetry' responses to parity at 3.75 Hz (7.5 Hz/2). Parity responses were probed with four different stimulus sets, increasing in intra-numeral stimulus variability, and with two control conditions composed of non-conceptual numeral alternations. Significant asymmetry responses were found over the occipitotemporal cortex to all conditions, even for the arbitrary controls. The large physical-differences control condition elicited the largest response in the stimulus set with the lowest variability (one font). Only in the stimulus set with the highest variability (20 drawn, coloured exemplars/numeral) did the response to parity surpass both control conditions. These findings show that physical differences across small sets of Arabic numerals can strongly influence, and even account for, automatic brain responses. However, carefully designed control conditions and highly variable stimulus sets may be used towards identifying truly conceptual neural responses.

Clinical characteristics, longitudinal adaptive functioning, and association with electroencephalogram activity in PPP2R5D-related neurodevelopmental disorder.

Protein phosphatase 2 regulatory subunit B56δ related neurodevelopmental disorder (PPP2R5D-related NDD) is largely caused by de novo heterozygous missense PPP2R5D variants. We report medical characteristics, longitudinal adaptive functioning, and in-person neurological, motor, cognitive, and electroencephalogram (EEG) activity for PPP2R5D-related NDD. Forty-two individuals (median age 6 years, range = 0.8-25.3) with pathogenic/likely pathogenic PPP2R5D variants were assessed, and almost all variants were missense (97.6%) and de novo (85.7%). Common clinical symptoms were developmental delay, hypotonia, macrocephaly, seizures, autism, behavioral challenges, and sleep problems. The mean Gross motor functional measure-66 was 60.2 ± 17.3% and the mean Revised upper limb module score was 25.9 ± 8.8. The Vineland-3 adaptive behavior composite score (VABS-3 ABC) at baseline was low (M = 61.7 ± 16.8). VABS-3 growth scale value scores increased from baseline in all subdomains (range = 0.6-5.9) after a mean follow-up of 1.3 ± 0.3 years. EEG beta and gamma power were negatively correlated with VABS-3 score; p < 0.05. Individuals had a mean Quality-of-life inventory-disability score of 74.7 ± 11.4. Twenty caregivers (80%) had a risk of burnout based on the Caregiver burden inventory. Overall, the most common clinical manifestations of PPP2R5D-related NDD were impaired cognitive, adaptive function, and motor skills; and EEG activity was associated with adaptive functioning. This clinical characterization describes the natural history in preparation for clinical trials.