Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes.

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers.

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.

Choice of Magnetometers and Gradiometers after Signal Space Separation.

BACKGROUND: Modern Elekta Neuromag MEG devices include 102 sensor triplets containing one magnetometer and two planar gradiometers. The first processing step is often a signal space separation (SSS), which provides a powerful noise reduction. A question commonly raised by researchers and reviewers relates to which data should be employed in analyses: (1) magnetometers only, (2) gradiometers only, (3) magnetometers and gradiometers together. The MEG community is currently divided with regard to the proper answer. METHODS: First, we provide theoretical evidence that both gradiometers and magnetometers result from the backprojection of the same SSS components. Then, we compare resting state and task-related sensor and source estimations from magnetometers and gradiometers in real MEG recordings before and after SSS. RESULTS: SSS introduced a strong increase in the similarity between source time series derived from magnetometers and gradiometers (r² = 0.3-0.8 before SSS and r² > 0.80 after SSS). After SSS, resting state power spectrum and functional connectivity, as well as visual evoked responses, derived from both magnetometers and gradiometers were highly similar (Intraclass Correlation Coefficient > 0.8, r² > 0.8). CONCLUSIONS: After SSS, magnetometer and gradiometer data are estimated from a single set of SSS components (usually ≤ 80). Equivalent results can be obtained with both sensor types in typical MEG experiments.

Test-retest reliability of resting-state magnetoencephalography power in sensor and source space.

Several studies have reported changes in spontaneous brain rhythms that could be used as clinical biomarkers or in the evaluation of neuropsychological and drug treatments in longitudinal studies using magnetoencephalography (MEG). There is an increasing necessity to use these measures in early diagnosis and pathology progression; however, there is a lack of studies addressing how reliable they are. Here, we provide the first test-retest reliability estimate of MEG power in resting-state at sensor and source space. In this study, we recorded 3 sessions of resting-state MEG activity from 24 healthy subjects with an interval of a week between each session. Power values were estimated at sensor and source space with beamforming for classical frequency bands: delta (2-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), low beta (13-20 Hz), high beta (20-30 Hz), and gamma (30-45 Hz). Then, test-retest reliability was evaluated using the intraclass correlation coefficient (ICC). We also evaluated the relation between source power and the within-subject variability. In general, ICC of theta, alpha, and low beta power was fairly high (ICC > 0.6) while in delta and gamma power was lower. In source space, fronto-posterior alpha, frontal beta, and medial temporal theta showed the most reliable profiles. Signal-to-noise ratio could be partially responsible for reliability as low signal intensity resulted in high within-subject variability, but also the inherent nature of some brain rhythms in resting-state might be driving these reliability patterns. In conclusion, our results described the reliability of MEG power estimates in each frequency band, which could be considered in disease characterization or clinical trials.

Multimodal description of whole brain connectivity: A comparison of resting state MEG, fMRI, and DWI.

Structural and functional connectivity (SC and FC) have received much attention over the last decade, as they offer unique insight into the coordination of brain functioning. They are often assessed independently with three imaging modalities: SC using diffusion-weighted imaging (DWI), FC using functional magnetic resonance imaging (fMRI), and magnetoencephalography/electroencephalography (MEG/EEG). DWI provides information about white matter organization, allowing the reconstruction of fiber bundles. fMRI uses blood-oxygenation level-dependent (BOLD) contrast to indirectly map neuronal activation. MEG and EEG are direct measures of neuronal activity, as they are sensitive to the synchronous inputs in pyramidal neurons. Seminal studies have targeted either the electrophysiological substrate of BOLD or the anatomical basis of FC. However, multimodal comparisons have been scarcely performed, and the relation between SC, fMRI-FC, and MEG-FC is still unclear. Here we present a systematic comparison of SC, resting state fMRI-FC, and MEG-FC between cortical regions, by evaluating their similarities at three different scales: global network, node, and hub distribution. We obtained strong similarities between the three modalities, especially for the following pairwise combinations: SC and fMRI-FC; SC and MEG-FC at theta, alpha, beta and gamma bands; and fMRI-FC and MEG-FC in alpha and beta. Furthermore, highest node similarity was found for regions of the default mode network and primary motor cortex, which also presented the highest hubness score. Distance was partially responsible for these similarities since it biased all three connectivity estimates, but not the unique contributor, since similarities remained after controlling for distance.

Qualitative differences in the spatiotemporal brain states supporting configural face processing emerge in adolescence in autism.

BACKGROUND: Studying the neural processing of faces can illuminate the mechanisms of compromised social expertise in autism. To resolve a longstanding debate, we examined whether differences in configural face processing in autism are underpinned by quantitative differences in the activation of typical face processing pathways, or the recruitment of non-typical neural systems. METHODS: We investigated spatial and temporal characteristics of event-related EEG responses to upright and inverted faces in a large sample of children, adolescents, and adults with and without autism. We examined topographic analyses of variance and global field power to identify group differences in the spatial and temporal response to face inversion. We then examined how quasi-stable spatiotemporal profiles - microstates - are modulated by face orientation and diagnostic group. RESULTS: Upright and inverted faces produced distinct profiles of topography and strength in the topographical analyses. These topographical profiles differed between diagnostic groups in adolescents, but not in children or adults. In the microstate analysis, the autistic group showed differences in the activation strength of normative microstates during early-stage processing at all ages, suggesting consistent quantitative differences in the operation of typical processing pathways; qualitative differences in microstate topographies during late-stage processing became prominent in adults, suggesting the increasing involvement of non-typical neural systems with processing time and over development. CONCLUSIONS: These findings suggest that early difficulties with configural face processing may trigger later compensatory processes in autism that emerge in later development.

From mechanisms to markers: novel noninvasive EEG proxy markers of the neural excitation and inhibition system in humans.

Brain function is a product of the balance between excitatory and inhibitory (E/I) brain activity. Variation in the regulation of this activity is thought to give rise to normal variation in human traits, and disruptions are thought to potentially underlie a spectrum of neuropsychiatric conditions (e.g., Autism, Schizophrenia, Downs' Syndrome, intellectual disability). Hypotheses related to E/I dysfunction have the potential to provide cross-diagnostic explanations and to combine genetic and neurological evidence that exists within and between psychiatric conditions. However, the hypothesis has been difficult to test because: (1) it lacks specificity-an E/I dysfunction could pertain to any level in the neural system- neurotransmitters, single neurons/receptors, local networks of neurons, or global brain balance - most researchers do not define the level at which they are examining E/I function; (2) We lack validated methods for assessing E/I function at any of these neural levels in humans. As a result, it has not been possible to reliably or robustly test the E/I hypothesis of psychiatric disorders in a large cohort or longitudinal patient studies. Currently available, in vivo markers of E/I in humans either carry significant risks (e.g., deep brain electrode recordings or using Positron Emission Tomography (PET) with radioactive tracers) and/or are highly restrictive (e.g., limited spatial extent for Transcranial Magnetic Stimulation (TMS) and Magnetic Resonance Spectroscopy (MRS). More recently, a range of novel Electroencephalography (EEG) features has been described, which could serve as proxy markers for E/I at a given level of inference. Thus, in this perspective review, we survey the theories and experimental evidence underlying 6 novel EEG markers and their biological underpinnings at a specific neural level. These cheap-to-record and scalable proxy markers may offer clinical utility for identifying subgroups within and between diagnostic categories, thus directing more tailored sub-grouping and, therefore, treatment strategies. However, we argue that studies in clinical populations are premature. To maximize the potential of prospective EEG markers, we first need to understand the link between underlying E/I mechanisms and measurement techniques.

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.

Exploring cognitive and biological correlates of sleep quality and their potential links with Alzheimer's disease (ALFASleep project): protocol for an observational study.

INTRODUCTION: The growing worldwide prevalence of Alzheimer's disease (AD) and the lack of effective treatments pose a dire medical challenge. Sleep disruption is also prevalent in the ageing population and is increasingly recognised as a risk factor and an early sign of AD. The ALFASleep project aims to characterise sleep with subjective and objective measurements in cognitively unimpaired middle/late middle-aged adults at increased risk of AD who are phenotyped with fluid and neuroimaging AD biomarkers. This will contribute to a better understanding of the pathophysiological mechanisms linking sleep with AD, thereby paving the way for the development of non-invasive biomarkers and preventive strategies targeting sleep. METHODS AND ANALYSIS: We will invite 200 participants enrolled in the ALFA+ (for ALzheimer and FAmilies) prospective observational study to join the ALFASleep study. ALFA+ participants are cognitively unimpaired middle-aged/late middle-aged adults who are followed up every 3 years with a comprehensive set of evaluations including neuropsychological tests, blood and cerebrospinal fluid (CSF) sampling, and MRI and positron emission tomography acquisition. ALFASleep participants will be additionally characterised with actigraphy and CSF-orexin-A measurements, and a subset (n=90) will undergo overnight polysomnography. We will test associations of sleep measurements and CSF-orexin-A with fluid biomarkers of AD and glial activation, neuroimaging outcomes and cognitive performance. In case we found any associations, we will test whether changes in AD and/or glial activation markers mediate the association between sleep and neuroimaging or cognitive outcomes and whether sleep mediates associations between CSF-orexin-A and AD biomarkers. ETHICS AND DISSEMINATION: The ALFASleep study protocol has been approved by the independent Ethics Committee Parc de Salut Mar, Barcelona (2018/8207/I). All participants have signed a written informed consent before their inclusion (approved by the same ethics committee). Study findings will be presented at national and international conferences and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04932473.

A Graph Gaussian Embedding Method for Predicting Alzheimer's Disease Progression With MEG Brain Networks.

Characterizing the subtle changes of functional brain networks associated with the pathological cascade of Alzheimer's disease (AD) is important for early diagnosis and prediction of disease progression prior to clinical symptoms. We developed a new deep learning method, termed multiple graph Gaussian embedding model (MG2G), which can learn highly informative network features by mapping high-dimensional resting-state brain networks into a low-dimensional latent space. These latent distribution-based embeddings enable a quantitative characterization of subtle and heterogeneous brain connectivity patterns at different regions, and can be used as input to traditional classifiers for various downstream graph analytic tasks, such as AD early stage prediction, and statistical evaluation of between-group significant alterations across brain regions. We used MG2G to detect the intrinsic latent dimensionality of MEG brain networks, predict the progression of patients with mild cognitive impairment (MCI) to AD, and identify brain regions with network alterations related to MCI.

FNS allows efficient event-driven spiking neural network simulations based on a neuron model supporting spike latency.

Neural modelling tools are increasingly employed to describe, explain, and predict the human brain's behavior. Among them, spiking neural networks (SNNs) make possible the simulation of neural activity at the level of single neurons, but their use is often threatened by the resources needed in terms of processing capabilities and memory. Emerging applications where a low energy burden is required (e.g. implanted neuroprostheses) motivate the exploration of new strategies able to capture the relevant principles of neuronal dynamics in reduced and efficient models. The recent Leaky Integrate-and-Fire with Latency (LIFL) spiking neuron model shows some realistic neuronal features and efficiency at the same time, a combination of characteristics that may result appealing for SNN-based brain modelling. In this paper we introduce FNS, the first LIFL-based SNN framework, which combines spiking/synaptic modelling with the event-driven approach, allowing us to define heterogeneous neuron groups and multi-scale connectivity, with delayed connections and plastic synapses. FNS allows multi-thread, precise simulations, integrating a novel parallelization strategy and a mechanism of periodic dumping. We evaluate the performance of FNS in terms of simulation time and used memory, and compare it with those obtained with neuronal models having a similar neurocomputational profile, implemented in NEST, showing that FNS performs better in both scenarios. FNS can be advantageously used to explore the interaction within and between populations of spiking neurons, even for long time-scales and with a limited hardware configuration.

Electrophysiological Phenotype in Angelman Syndrome Differs Between Genotypes.

BACKGROUND: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by either disruptions of the gene UBE3A or deletion of chromosome 15 at 15q11-q13, which encompasses UBE3A and several other genes, including GABRB3, GABRA5, GABRG3, encoding gamma-aminobutyric acid type A receptor subunits (ß3, α5, γ3). Individuals with deletions are generally more impaired than those with other genotypes, but the underlying pathophysiology remains largely unknown. Here, we used electroencephalography (EEG) to test the hypothesis that genes other than UBE3A located on 15q11-q13 cause differences in pathophysiology between AS genotypes. METHODS: We compared spectral power of clinical EEG recordings from children (1-18 years of age) with a deletion genotype (n = 37) or a nondeletion genotype (n = 21) and typically developing children without Angelman syndrome (n = 48). RESULTS: We found elevated theta power (peak frequency: 5.3 Hz) and diminished beta power (peak frequency: 23 Hz) in the deletion genotype compared with the nondeletion genotype as well as excess broadband EEG power (1-32 Hz) peaking in the delta frequency range (peak frequency: 2.8 Hz), shared by both genotypes but stronger for the deletion genotype at younger ages. CONCLUSIONS: Our results provide strong evidence for the contribution of non-UBE3A neuronal pathophysiology in deletion AS and suggest that hemizygosity of the GABRB3-GABRA5-GABRG3 gene cluster causes abnormal theta and beta EEG oscillations that may underlie the more severe clinical phenotype. Our work improves the understanding of AS pathophysiology and has direct implications for the development of AS treatments and biomarkers.

Patients with autism spectrum disorders display reproducible functional connectivity alterations.

Despite the high clinical burden, little is known about pathophysiology underlying autism spectrum disorder (ASD). Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchronization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance of these alterations. Here, we addressed these questions in four large ASD cohorts. Using rs-fMRI, we identified functional connectivity alterations associated with ASD. We tested for associations of these imaging phenotypes with clinical and demographic factors such as age, sex, medication status, and clinical symptom severity. Our results showed reproducible patterns of ASD-associated functional hyper- and hypoconnectivity. Hypoconnectivity was primarily restricted to sensory-motor regions, whereas hyperconnectivity hubs were predominately located in prefrontal and parietal cortices. Shifts in cortico-cortical between-network connectivity from outside to within the identified regions were shown to be a key driver of these abnormalities. This reproducible pathophysiological phenotype was partially associated with core ASD symptoms related to communication and daily living skills and was not affected by age, sex, or medication status. Although the large effect sizes in standardized cohorts are encouraging with respect to potential application as a treatment and for patient stratification, the moderate link to clinical symptoms and the large overlap with healthy controls currently limit the usability of identified alterations as diagnostic or efficacy readout.

Tracking the effect of emotional distraction in working memory brain networks: Evidence from an MEG study.

The active maintenance of information in visual working memory (WM) is known to rely on the sustained activity over functional networks including frontal, parietal, occipital, and temporal cortices. Previous studies have described interference-based disturbances in the functional coupling between prefrontal and posterior cortices, and that such disturbances can be restored for a successful WM performance after the presentation of the interfering stimulus. However, very few studies have applied functional connectivity measures to the analysis of the brain dynamics involved in overriding emotional distraction, and all of them have limited their analysis to the particular connections between the amygdala and prefrontal cortex. In this study, we used magnetoencephalography (MEG) to characterize the mutual information-based functional connectivity dynamics among regions of interest located over the prefrontal, the parietal, the temporal, and the occipital cortex. Our results show that the detection of emotional distraction at early latencies (50-150 ms) induces a reduction of functional connectivity involving parietal and temporal cortices that are part of the frontoposterior WM network, while functional coupling among prefrontal areas and between them and posterior cortices is strengthened during the detection of emotional distractors. Later in the processing of the distractor (250-350 and 360-460 ms), the frontoposterior coupling is reestablished for a successful performance, while the orbitofrontal and ventrolateral prefrontal cortex become strongly connected to posterior cortices as a mechanism to cope with emotional distractors.

Network Disruption in the Preclinical Stages of Alzheimer's Disease: From Subjective Cognitive Decline to Mild Cognitive Impairment.

INTRODUCTION: Subjective Cognitive Decline (SCD) is a largely unknown state thought to represent a preclinical stage of Alzheimer's Disease (AD) previous to mild cognitive impairment (MCI). However, the course of network disruption in these stages is scarcely characterized. METHODS: We employed resting state magnetoencephalography in the source space to calculate network smallworldness, clustering, modularity and transitivity. Nodal measures (clustering and node degree) as well as modular partitions were compared between groups. RESULTS: The MCI group exhibited decreased smallworldness, clustering and transitivity and increased modularity in theta and beta bands. SCD showed similar but smaller changes in clustering and transitivity, while exhibiting alterations in the alpha band in opposite direction to those showed by MCI for modularity and transitivity. At the node level, MCI disrupted both clustering and nodal degree while SCD showed minor changes in the latter. Additionally, we observed an increase in modular partition variability in both SCD and MCI in theta and beta bands. CONCLUSION: SCD elders exhibit a significant network disruption, showing intermediate values between HC and MCI groups in multiple parameters. These results highlight the relevance of cognitive concerns in the clinical setting and suggest that network disorganization in AD could start in the preclinical stages before the onset of cognitive symptoms.

Functional Connectivity Disruption in Subjective Cognitive Decline and Mild Cognitive Impairment: A Common Pattern of Alterations.

Functional connectivity (FC) alterations represent a key feature in Alzheimer's Disease (AD) and provide a useful tool to characterize and predict the course of the disease. Those alterations have been also described in Mild Cognitive Impairment (MCI), a prodromal stage of AD. There is a growing interest in detecting AD pathology in the brain in the very early stages of the disorder. Subjective Cognitive Decline (SCD) could represent a preclinical asymptomatic stage of AD but very little is known about this population. In the present work we assessed whether FC disruptions are already present in this stage, and if they share any spatial distribution properties with MCI alterations (a condition known to be highly related to AD). To this end, we measured electromagnetic spontaneous activity with MEG in 39 healthy control elders, 41 elders with SCD and 51 MCI patients. The results showed FC alterations in both SCD and MCI compared to the healthy control group. Interestingly, both groups exhibited a very similar spatial pattern of altered links: a hyper-synchronized anterior network and a posterior network characterized by a decrease in FC. This decrease was more pronounced in the MCI group. These results highlight that elders with SCD present FC alterations. More importantly, those disruptions affected AD typically related areas and showed great overlap with the alterations exhibited by MCI patients. These results support the consideration of SCD as a preclinical stage of AD and may indicate that FC alterations appear very early in the course of the disease.

The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders.

BACKGROUND: The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. METHODS: LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. RESULTS: Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some 'lessons learnt'. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). CONCLUSION: We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies.

The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation.

BACKGROUND: The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. METHODS: From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. RESULTS: The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females. CONCLUSIONS: The established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials.

Quantifying the Test-Retest Reliability of Magnetoencephalography Resting-State Functional Connectivity.

The coordinated activity of the resting-state brain can be evaluated with magnetoencephalography (MEG) for distinct brain rhythms by performing source reconstruction to estimate the activities of target brain regions and employing one of the many existent functional connectivity (FC) algorithms. Although this procedure has been applied in a great amount of studies both with healthy and pathological populations, the reliability of such FC estimates is unknown, and this impairs the use of resting-state MEG FC at the individual level. In this study, the test-retest reliability of MEG resting FC was evaluated by exploring both within- and between-subject variability in FC in 16 healthy subjects who underwent three resting-state MEG scans. FC was computed after beamforming source reconstruction with four popular FC metrics: phase-locking value (PLV), phase lag index (PLI), direct envelope correlation (d-ecor), and envelope correlation with leakage correction (lc-ecor). Then, test-restest reliability and within- and between-subject agreement were evaluated with the intraclass correlation coefficient (ICC) and Kendall's W, respectively. Reliability was found to depend on the FC metric, the frequency band, and the specific link. As a general trend, greater test-retest reliability was found for PLV in theta to gamma, and for lc-ecor and d-ecor in beta. Further inspection of the ICC distribution revealed that volume conduction effects could be contributing to high ICC in PLV and d-ecor. In addition, stronger links were found to be more reliable. Overall, this encourages the further use of resting-state MEG FC for individual-level studies, especially with PLV or envelope correlation metrics.

Early detection and late cognitive control of emotional distraction by the prefrontal cortex.

Unpleasant emotional distraction can impair the retention of non-emotional information in working memory (WM). Research links the prefrontal cortex with the successful control of such biologically relevant distractors, although the temporal changes in this brain mechanism remain unexplored. We use magnetoencephalography to investigate the temporal dynamics of the cognitive control of both unpleasant and pleasant distraction, in the millisecond (ms) scale. Behavioral results demonstrate that pleasant events do not affect WM maintenance more than neutral ones. Neuroimaging results show that prefrontal cortices are recruited for the rapid detection of emotional distraction, at early latencies of the processing (70-130 ms). Later in the processing (360-450 ms), the dorsolateral, the medial and the orbital sections of the prefrontal cortex mediate the effective control of emotional distraction. In accordance with the behavioral performance, pleasant distractors do not require higher prefrontal activity than neutral ones. These findings extend our knowledge about the brain mechanisms of coping with emotional distraction in WM. In particular, they show for the first time that overriding the attentional capture triggered by emotional distractors, while maintaining task-relevant elements in mind, is based on the early detection of such linked-to-survival information and on its later cognitive control by the prefrontal cortex.