Auditory white noise exposure results in intrinsic cortical excitability changes.

Cortical excitability is commonly measured by applying magnetic stimulation in combination with measuring behavioral response. This measure has, however, some shortcomings including spatial limitation to the primary motor cortex and not accounting for intrinsic excitability fluctuations. Here, we use a measure for intrinsic excitability based on phase synchronization previously validated for epilepsy. We apply this measure in 30 healthy participants' magnetoencephalography (MEG) recordings during the exposure of auditory white noise, a stimulus that has been suggested to modify cortical excitability. Using cortical parcellation of the MEG source data, we could find a specific pattern of increased and decreased excitability while participants are exposed to white noise vs. silence. Specifically, excitability during white noise exposure decreases in the frontal lobe and increases in the temporal lobe. This study thus adds to the understanding of cortical excitability changes due to specific environmental stimuli as well as the spatial extent of these effects.

[Formula: see text]FarmApp: a new assessment of cognitive control and memory for children and young people with neurodevelopmental difficulties.

We introduce a new touchscreen-based method measuring aspects of cognitive control and memory, in children and young people with neurodevelopmental difficulties, including intellectual disability (ID). FarmApp is a gamified, tablet-based assessment tool measuring go/no-go response speed, response inhibition, visuospatial short-term memory span, and long-term memory. Here, we assessed the feasibility, validity, and utility of the method, including the benefits of measuring change in performance over two weeks. We observed that: 1) a higher proportion of participants completed FarmApp than traditional psychometric tests; 2) this proportion increased when participants had opportunity for two weeks of self-paced testing at home; 3) ADHD-relevant behavioral difficulties were associated with average go/no-go performance across all attempts, and change in go/no-go performance over time, indicating sensitivity of the method to cognitive differences with real-world relevance. We also addressed the potential utility of the FarmApp for exploring links between ID etiology and cognitive processes. We observed differences in go/no-go task between two groups of ID participants stratified by the physiological functions of associated genetic variants (chromatin-related and synaptic-related). Moreover, the synaptic group demonstrated higher degree of improvement in go/no-go performance over time. This outcome is potentially informative of dynamic mechanisms contributing to cognitive difficulties within this group. In sum, FarmApp is a feasible, valid, and useful tool increasing access to cognitive assessment for individuals with neurodevelopmental difficulties of variable severity, with an added opportunity to monitor variation in performance over time and determine capacity to acquire task competence.

The neurodevelopmental spectrum of synaptic vesicle cycling disorders.

In this review, we describe and discuss neurodevelopmental phenotypes arising from rare, high penetrance genomic variants which directly influence synaptic vesicle cycling (SVC disorders). Pathogenic variants in each SVC disorder gene lead to disturbance of at least one SVC subprocess, namely vesicle trafficking (e.g. KIF1A and GDI1), clustering (e.g. TRIO, NRXN1 and SYN1), docking and priming (e.g. STXBP1), fusion (e.g. SYT1 and PRRT2) or re-uptake (e.g. DNM1, AP1S2 and TBC1D24). We observe that SVC disorders share a common set of neurological symptoms (movement disorders, epilepsies), cognitive impairments (developmental delay, intellectual disabilities, cerebral visual impairment) and mental health difficulties (autism, ADHD, psychiatric symptoms). On the other hand, there is notable phenotypic variation between and within disorders, which may reflect selective disruption to SVC subprocesses, spatiotemporal and cell-specific gene expression profiles, mutation-specific effects, or modifying factors. Understanding the common cellular and systems mechanisms underlying neurodevelopmental phenotypes in SVC disorders, and the factors responsible for variation in clinical presentations and outcomes, may translate to personalized clinical management and improved quality of life for patients and families.

Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study.

BACKGROUND: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants. METHODS: Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n = 29) or chromatin regulation (n = 23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components-Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks. RESULTS: We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety. LIMITATIONS: Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups. CONCLUSION: We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful.

Functional network dynamics in a neurodevelopmental disorder of known genetic origin.

Dynamic connectivity in functional brain networks is a fundamental aspect of cognitive development, but we have little understanding of the mechanisms driving variability in these networks. Genes are likely to influence the emergence of fast network connectivity via their regulation of neuronal processes, but novel methods to capture these rapid dynamics have rarely been used in genetic populations. The current study redressed this by investigating brain network dynamics in a neurodevelopmental disorder of known genetic origin, by comparing individuals with a ZDHHC9-associated intellectual disability to individuals with no known impairment. We characterised transient network dynamics using a Hidden Markov Model (HMM) on magnetoencephalography (MEG) data, at rest and during auditory oddball stimulation. The HMM is a data-driven method that captures rapid patterns of coordinated brain activity recurring over time. Resting-state network dynamics distinguished the groups, with ZDHHC9 participants showing longer state activation and, crucially, ZDHHC9 gene expression levels predicted the group differences in dynamic connectivity across networks. In contrast, network dynamics during auditory oddball stimulation did not show this association. We demonstrate a link between regional gene expression and brain network dynamics, and present the new application of a powerful method for understanding the neural mechanisms linking genetic variation to cognitive difficulties.

Neurophysiological Correlates of Featural and Spacing Processing for Face and Non-face Stimuli.

The peculiar ability of humans to recognize hundreds of faces at a glance has been attributed to face-specific perceptual mechanisms known as holistic processing. Holistic processing includes the ability to discriminate individual facial features (i.e., featural processing) and their spatial relationships (i.e., spacing processing). Here, we aimed to characterize the spatio-temporal dynamics of featural- and spacing-processing of faces and objects. Nineteen healthy volunteers completed a newly created perceptual discrimination task for faces and objects (i.e., the "University of East London Face Task") while their brain activity was recorded with a high-density (128 electrodes) electroencephalogram. Our results showed that early event related potentials at around 100 ms post-stimulus onset (i.e., P100) are sensitive to both facial features and spacing between the features. Spacing and features discriminability for objects occurred at circa 200 ms post-stimulus onset (P200). These findings indicate the existence of neurophysiological correlates of spacing vs. features processing in both face and objects, and demonstrate faster brain processing for faces.

Neurosensory effects of transcranial alternating current stimulation.

BACKGROUND: Electrical brain stimulation can elicit neurosensory side effects that are unrelated to the intended stimulation effects. This presents a challenge when designing studies with blinded control conditions. OBJECTIVE: The aim of this research was to investigate the role of different transcranial alternating current stimulation (tACS) parameters, i.e. intensity, frequency, and electrode montage, on the probability, duration and intensity of elicited neurosensory side effects. METHODS: In a first study, we examined the influence of tACS on sensations of phosphenes, dizziness, pressure, and skin sensation in fifteen healthy subjects, during 8 s of stimulation with different amplitudes (1500 µA, 1000 µA, 500 µA, 250 µA), frequencies (2 Hz, 4 Hz, 8 Hz, 16 Hz, 32 Hz, 64 Hz), and montages (F3/F4, F3/C4, F3/P4, P3/F4, P3/C4, P3/P4). In a second study, ten healthy subjects were exposed to 60 s of tACS (1000 µA, 2 Hz versus 16 Hz, F3/F4 versus P3/P4) and were asked to rate the intensity of sensations every 12 s. RESULTS: The first study showed that all stimulation parameters had an influence on the probability and intensity of sensations. Phosphenes were most likely and strongest for frontal montages and higher frequencies. Dizziness was most likely and strongest for parietal montages and at stimulation frequency of 4 Hz. Skin sensations and pressure was more likely when stimulation was performed across central regions and at posterior montages, respectively. The second study also revealed that the probability and the intensity of sensations were neither modified during more extended periods of stimulation nor affected by carry-over effects. CONCLUSION: We demonstrated that the strength and the likelihood of sensations elicited by tACS were specifically modulated by the stimulation parameters. The present work may therefore be instrumental in establishing effective blinding conditions for studies with tACS.