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Background and purposeDeletion and duplication of chromosome 16p11.2 (BP4-BP5) have been associated with developmental disorders such as autism spectrum disorders, and deletion subjects exhibit a large (20-ms) delay of the auditory evoked cortical response as measured by magnetoencephalography (M100 latency). The purpose of this study was to use a multimodal approach to test whether changes in white matter microstructure are associated with delayed M100 latency.Materials and methodsThirty pediatric deletion carriers, 9 duplication carriers, and 39 control children were studied with both magnetoencephalography and diffusion MR imaging. The M100 latency and auditory system DTI measures were compared between groups and tested for correlation.ResultsIn controls, white matter diffusivity significantly correlated with the speed of the M100 response. However, the relationship between structure and function appeared uncoupled in 16p11.2 copy number variation carriers. The alterations to auditory system white matter microstructure in the 16p11.2 deletion only partially accounted for the 20-ms M100 delay. Although both duplication and deletion groups exhibit abnormal white matter microstructure, only the deletion group has delayed M100 latency.ConclusionsThese results indicate that gene dosage impacts factors other than white matter microstructure, which modulate conduction velocity.

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Latency of electric (e.g., PI and NI) and magnetic (e.g., M100) auditory evoked components depends on age in typically developing children, with longer latencies for younger (4-6 years) and shorter, adult-like latencies for older (14-16 years) children. Age-related changes in evoked components provide indirect measures of auditory system maturation and reflect changes that occur during development. We use magnetoencephalography (MEG) to investigate maturational changes in cortical auditory systems in left (LH) and right (RH) hemispheres in children with autism disorder (AD) and Controls. We recorded auditory evoked responses over left and right temporal lobes in 17 Control and 15 AD children in the age range 8-16 years and measured M100 latency as a function of age, subject group and hemisphere. Linear regression analyses of age and M100 latency provided an estimate of the rate of latency change (ms/year) by hemisphere and subject group. Controls: M100 latency for the group ranged from 100.8 to 166.1 ms and varied linearly in both hemispheres, decreasing at a rate of -4 ms/year (LH) and -4.5 ms/year (RH). AD: M100 latency ranged from 116.2 to 186.2 ins. Slopes of regression lines did not differ from zero in either LH or RH. M100 latency showed a tendency to vary with age in LH, decreasing at a rate of -4.6 ms/year. M100 latency in RH increased slightly (at a rate of 0.8 ms/year) with age. Results provide evidence for a differential auditory system development in AD children which may reflect abnormalities in cortical maturational processes in AD. (C) 2003 Elsevier B.V. All rights reserved.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder and presents with challenges in social communication. A hypothesized underlying contributing mechanism is the imbalance in excitation and inhibition (E/I), partly influenced by the levels of excitatory neurotransmitter glutamate (Glu) and inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain. Although many have reported the levels of GABA and Glu in the brain, only a few reports address the temporal cortex and then only with a small sample of autistic children, and often only in one hemisphere. We used a macromolecular suppressed edited-magnetic resonance spectroscopy (MRS) sequence to study GABA and Glu (as potential key players influencing E/I) in a large sample of children with ASD in the right and left temporal cortices of children with (N = 56) and without (N = 30) ASD (7-18 years). As a group, children with ASD exhibited no differences in the left hemisphere (GABA and Glu Cohen's |d|: 0.24 and 0.03), but the right hemisphere showed higher GABA and lower Glu concentrations (GABA and Glu Cohen's |d|: 0.53 and 0.65) compared to neurotypicals. Furthermore, a negative association was found between the right hemisphere Glu levels of the ASD group and a clinical assessment tool (r = -0.361, p = 0.022), reflecting autism trait severity (social responsiveness scale). In conclusion, we highlight the chemical abnormalities in children with ASD through a cross-sectional measurement. Longitudinal studies are warranted to determine whether these chemical levels persist or resolve over development., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Background: In school-age children, the myelination of the auditory radiation thalamocortical pathway is associated with the latency of auditory evoked responses, with the myelination of thalamocortical axons facilitating the rapid propagation of acoustic information. Little is known regarding this auditory system function-structure association in infants and toddlers., Methods and Participants: The present study tested the hypothesis that maturation of auditory radiation white-matter microstructure (e.g., fractional anisotropy (FA); measured using diffusion-weighted MRI) is associated with the latency of the infant auditory response (the P2m response, measured using magnetoencephalography, MEG) in a cross-sectional (N = 47, 2 to 24 months, 19 females) as well as longitudinal cohort (N = 18, 2 to 29 months, 8 females) of typically developing infants and toddlers. Of 18 longitudinal infants, 2 infants had data from 3 timepoints and 16 infants had data from 2 timepoints., Results: In the cross-sectional sample, non-linear maturation of P2m latency and auditory radiation diffusion measures were observed. Auditory radiation diffusion accounted for significant variance in P2m latency, even after removing the variance associated with age in both P2m latency and auditory radiation diffusion measures. In the longitudinal sample, latency and FA associations could be observed at the level of a single child., Conclusions: Findings provide strong support for the hypothesis that an increase in thalamocortical neural conduction velocity, due to increased axon diameter and/or myelin maturation, contributes to a decrease in the infant P2m auditory evoked response latency., Significance: Infant multimodal brain imaging identifies brain mechanisms contributing to the rapid changes in neural circuit activity during the first two years of life., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: This study was undertaken to characterize quantitative electroencephalographic (EEG) features in participants from the Natural history study of RTT and Related Disorders and to assess the potential for these features to act as objective measures of cortical function for Rett syndrome (RTT)., Methods: EEG amplitude and power features were derived from the resting EEG of 60 females with RTT (median age = 10.7 years) and 26 neurotypical females (median age = 10.6 years). Analyses focus on group differences and within the RTT group, associations between the EEG parameters and clinical severity. For a subset of participants (n = 20), follow-up data were available for assessing the reproducibility of the results and the stability in the parameters over 1 year., Results: Compared to neurotypical participants, participants with RTT had greater amplitude variability and greater low-frequency activity as reflected by greater delta power, more negative 1/f slope, and lower theta/delta, alpha/delta, beta/delta, alpha/theta, and beta/theta ratios. Greater delta power, more negative 1/f slope, and lower power ratios were associated with greater severity. Analyses of year 1 data replicated the associations between 1/f slope and power ratios and clinical severity and demonstrated good within-subject consistency in these measures., Interpretation: Overall, group comparisons reflected a greater predominance of lower versus higher frequency activity in participants with RTT, which is consistent with prior clinical interpretations of resting EEG in this population. The observed associations between the EEG power measures and clinical assessments and the repeatability of these measures underscore the potential for EEG to provide an objective measure of cortical function and clinical severity for RTT. ANN NEUROL 2024;96:175-186., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Youth with neurofibromatosis type I (NF1) demonstrate high rates of Autism Spectrum Disorder (ASD) and Attention Deficit/Hyperactivity Disorder (ADHD), which often have overlapping behaviors. Diagnostic clarity is important to guide services. This study evaluated ASD classification in NF1 using various methods and whether those with ADHD suspicion have more social challenges associated with ASD., Method: 34 youth with NF1 ( M age  = 10.5 ± 1.6 years), completed ASD assessments that combined direct observation and informant ratings to yield a Clinician Best Estimate (CBE) classification. Caregivers rated ASD-related social challenges using the Social Responsiveness Scale- 2 nd Edition (SRS-2)., Results: ASD classification varied depending on the method, ranging from 32% using low-threshold SRS-2 cut-scores (T ≥ 60) to under 6% when combining cut scores for diagnostic observational tools and stringent SRS-2 cut-scores (T ≥ 70). 14.7% had a CBE ASD classification. 44% were judged to have autism traits associated with a non-ASD diagnosis. The 52.9% with a suspicion of ADHD had higher SRS-2 scores than those without ADHD, F (7, 26) = 3.45, p < .05, Wilk's lambda = 0.518, partial eta squared = 0.482., Conclusions: Findings highlight the importance of rigorous diagnostic methodology when evaluating ASD in NF1 to inform the selection of targeted interventions for socialization challenges in NF1.

Resting-state alpha brain rhythms provide a foundation for basic as well as higher-order brain processes. Research suggests atypical maturation of the peak frequency of resting-state alpha activity (= PAF) in autism spectrum disorder (ASD). The present study examined resting-state alpha activity in young school-aged children, obtaining magnetoencephalographic (MEG) eyes-closed resting-state data from 47 typically developing (TD) males and 45 ASD males 6.0 to 9.3 years old. Results confirmed a higher PAF in ASD versus TD, and demonstrated that alpha power differences between groups were linked to the shift of PAF in ASD. Additionally, a higher PAF was associated with better cognitive performance in TD but not ASD. Finding thus suggested functional consequences of group differences in resting-state alpha activity., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To demonstrate J-difference coediting of glutamate using Hadamard encoding and reconstruction of Mescher-Garwood-edited spectroscopy (HERMES)., Methods: Density-matrix simulations of HERMES (TE 80 ms) and 1D J-resolved (TE 31-229 ms) of glutamate (Glu), glutamine (Gln), γ-aminobutyric acid (GABA), and glutathione (GSH) were performed. HERMES comprised four sub-experiments with editing pulses applied as follows: (A) 1.9/4.56 ppm simultaneously (ON GABA /ON GSH ); (B) 1.9 ppm only (ON GABA /OFF GSH ); (C) 4.56 ppm only (OFF GABA /ON GSH ); and (D) 7.5 ppm (OFF GABA /OFF GSH ). Phantom HERMES and 1D J-resolved experiments of Glu were performed. Finally, in vivo HERMES (20-ms editing pulses) and 1D J-resolved (TE 31-229 ms) experiments were performed on 137 participants using 3 T MRI scanners. LCModel was used for quantification., Results: HERMES simulation and phantom experiments show a Glu-edited signal at 2.34 ppm in the Hadamard sum combination A+B+C+D with no overlapping Gln signal. The J-resolved simulations and phantom experiments show substantial TE modulation of the Glu and Gln signals across the TEs, whose average yields a well-resolved Glu signal closely matching the Glu-edited signal from the HERMES sum spectrum. In vivo quantification of Glu show that the two methods are highly correlated (p < 0.001) with a bias of ∼10%, along with similar between-subject coefficients of variation (HERMES/TE-averaged: ∼7.3%/∼6.9%). Other Hadamard combinations produce the expected GABA-edited (A+B-C-D) or GSH-edited (A-B+C-D) signal., Conclusion: HERMES simulation and phantom experiments show the separation of Glu from Gln. In vivo HERMES experiments yield Glu (without Gln), GABA, and GSH in a single MRS scan., (© 2023 International Society for Magnetic Resonance in Medicine.)

There is no simple blood test for autism. Consequently, much attention has been paid to identifying noninvasive biomarkers using imaging (e.g., Magnetic resonance imaging, MRI) and electrophysiological (e.g., electroencephalography, EEG and magnetoencephalography, MEG) methods. While, in general, these lack direct biological specificity, they can (in principle) provide a useful tool, or suite of tools, for diagnostic, prognostic, stratification, and response monitoring purposes.This chapter focuses on the pursuit of biomarkers using magnetoencephalography (MEG). While closely related to the more common electroencephalography (EEG), MEG offers some unique characteristics (such as improved spatial resolution, in combination with real-time temporal resolution and spectral discrimination), that might be considered impactful in the pursuit of biomarkers.Given the widely-acknowledged heterogeneity of ASD ("if you've seen one child with autism, then you've seen one child with autism"), the tide of research is perhaps shifting away from diagnostic biomarkers toward biomarkers that can help stratify patients according to some similarity in biological basis, etiology, or pathway. This approach, somewhat pragmatic, may be of benefit when designing and conducting clinical trials of putative therapeutics, or when optimally designing behavioral supports (when "therapy" may not be indicated).Ultimately, MEG-derived biomarkers, however advantageous in themselves, may likely find a place as reference in the prioritization and roll-out of candidate biomarkers established using other modalities, more accessible and available to the global community., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Maturation of auditory cortex neural encoding processes was assessed in children with typical development (TD) and autism. Children 6-9 years old were enrolled at Time 1 (T1), with follow-up data obtained ~ 18 months later at Time 2 (T2), and ~ 36 months later at Time 3 (T3). Findings suggested an initial period of rapid auditory cortex maturation in autism, earlier than TD (prior to and surrounding the T1 exam), followed by a period of faster maturation in TD than autism (T1-T3). As a result of group maturation differences, post-stimulus group differences were observed at T1 but not T3. In contrast, stronger pre-stimulus activity in autism than TD was found at all time points, indicating this brain measure is stable across time., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Noninvasive alternatives to biopsy for assessment of interstitial fibrosis and tubular atrophy (IFTA), the major determinant of kidney transplant failure, remain profoundly limited. Elastography is a noninvasive technique that propagates shear waves across tissues to measure their stiffness. We aimed to test utility of elastography for early detection of IFTA in pediatric kidney allografts., Methods: We compared ultrasound (USE) and MR elastography (MRE) stiffness measurements, performed on pediatric transplant recipients referred for clinically indicated biopsies, and healthy controls., Results: Ten transplant recipients (median age 16 years) and eight controls (median age 16.5 years) were enrolled. Three transplant recipients had "stable" allografts and seven had Banff Grade 1 IFTA. Median time from transplantation to biopsy was 12 months. Mean estimated glomerular filtration rate was 61.5 mL/min/1.73m 2 by creatinine-cystatin-C CKiD equation at time of biopsy. Mean stiffness, calculated through one-way ANOVA, was higher for IFTA allografts (23.4 kPa USE/5.6 kPa MRE) than stable allografts (13.7 kPa USE/4.4 kPa MRE) and controls (9.1 kPa USE/3.6 kPa MRE). Pearson's coefficient between USE and MRE stiffness values was strong (r = .97). AUC for fibrosis prediction in transplanted kidneys was high for both modalities (0.91 USE and 0.89 MRE), although statistically nonsignificant (p > .05). Stiffness cut-off values for USE and MRE were 13.8 kPa and 4.6 kPa, respectively. Both values yielded a sensitivity of 100% but USE specificity (72%) was slightly higher than MRE (67%)., Conclusion: Elastography shows potential for detection of low-grade IFTA in allografts although a larger sample is imperative for clinical validation., (© 2023 Wiley Periodicals LLC.)

The infant auditory system rapidly matures across the first years of life, with a primary goal of obtaining ever-more-accurate real-time representations of the external world. Our understanding of how left and right auditory cortex neural processes develop during infancy, however, is meager, with few studies having the statistical power to detect potential hemisphere and sex differences in primary/secondary auditory cortex maturation. Using infant magnetoencephalography (MEG) and a cross-sectional study design, left and right auditory cortex P2m responses to pure tones were examined in 114 typically developing infants and toddlers (66 males, 2 to 24 months). Non-linear maturation of P2m latency was observed, with P2m latencies decreasing rapidly as a function of age during the first year of life, followed by slower changes between 12 and 24 months. Whereas in younger infants auditory tones were encoded more slowly in the left than right hemisphere, similar left and right P2m latencies were observed by ∼21 months of age due to faster maturation rate in the left than right hemisphere. No sex differences in the maturation of the P2m responses were observed. Finally, an earlier left than right hemisphere P2m latency predicted better language performance in older infants (12 to 24 months). Findings indicate the need to consider hemisphere when examining the maturation of auditory cortex neural activity in infants and toddlers and show that the pattern of left-right hemisphere P2m maturation is associated with language performance., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

In a relaxed and awake state with the eyes closed, 8-12 Hz neural oscillations are the dominant rhythm, most prominent in parietal-occipital regions. Resting-state (RS) alpha is associated with processing speed and is also thought to be central to how networks process information. Unfortunately, the RS eyes-closed (EC) exam can only be used with individuals who can remain awake with their eyes closed for an extended period. As such, infants, toddlers, and individuals with intellectual disabilities are usually excluded from RS alpha studies. Previous research suggests obtaining RS alpha measures in a dark room with the eyes open as a viable alternative to the traditional RS EC exam. To further explore this, RS EC and RS dark room (DR) eyes-open alpha activity was recorded using magnetoencephalography in children with typical development (TD; N = 37) and children with autism spectrum disorder (ASD; N = 30) 6.9-12.6 years old. Findings showed good reliability for the RS EC and DR peak alpha frequency (frequency with strongest alpha power; interclass correlation (ICC) = 0.83). ICCs for posterior alpha power were slightly lower (ICCs in the 0.70 s), with an ~ 5% reduction in posterior alpha power in the DR than EC condition. No differences in the EC and DR associations were observed between the TD and ASD groups. Finally, age was associated with both EC and DR peak alpha frequency. Findings thus indicate the DR exam as a viable way to obtain RS alpha measures in populations frequently excluded from electrophysiology RS studies., (© 2023 Society for Psychophysiological Research.)

Introduction: The M50 electrophysiological auditory evoked response time can be measured at the superior temporal gyrus with magnetoencephalography (MEG) and its latency is related to the conduction velocity of auditory input passing from ear to auditory cortex. In children with autism spectrum disorder (ASD) and certain genetic disorders such as XYY syndrome, the auditory M50 latency has been observed to be elongated (slowed)., Methods: The goal of this study is to use neuroimaging (diffusion MR and GABA MRS) measures to predict auditory conduction velocity in typically developing (TD) children and children with autism ASD and XYY syndrome., Results: Non-linear TD support vector regression modeling methods accounted for considerably more M50 latency variance than linear models, likely due to the non-linear dependence on neuroimaging factors such as GABA MRS. While SVR models accounted for ~80% of the M50 latency variance in TD and the genetically homogenous XYY syndrome, a similar approach only accounted for ~20% of the M50 latency variance in ASD, implicating the insufficiency of diffusion MR, GABA MRS, and age factors alone. Biologically based stratification of ASD was performed by assessing the conformance of the ASD population to the TD SVR model and identifying a sub-population of children with unexpectedly long M50 latency., Discussion: Multimodal integration of neuroimaging data can help build a mechanistic understanding of brain connectivity. The unexplained M50 latency variance in ASD motivates future hypothesis generation and testing of other contributing biological factors., Competing Interests: TR discloses consulting/medical advisory board association with Prism Clinical Imaging, Spago Nanomedicine, Avexis Inc., Acadia Pharmaceuticals, Proteus Neurodynamics and Fieldline Inc. TR and JE also disclose intellectual property relating to use of MEG as a biomarker in ASD. JB discloses consulting activity with McGowan Associates. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Berman, Bloy, Blaskey, Jackel, Miller, Ross, Edgar and Roberts.)

A vascularized composite tissue allotransplantation (VCA) was performed at the Children's Hospital of Philadelphia (CHOP), on an 8-year-old patient in 2015, six years after bilateral hand and foot amputation. Hand VCA resulted in reafferentation of the medial, ulnar, and radial nerves serving hand somatosensation and motor function. We used magnetoencephalography (MEG) to assess somatosensory cortical plasticity following the post-transplantation recovery of the peripheral sensory nerves of the hands. Our 2-year postoperative MEG showed that somatosensory lip representations, initially observed at "hand areas", reverted to canonical, orthotopic lip locations with recovery of post-transplant hand function. Here, we continue the assessment of motor and somatosensory responses up to 6-years post-transplant. Magnetoencephalographic somatosensory responses were recorded eight times over a six-year period following hand transplantation, using a 275-channel MEG system. Somatosensory tactile stimuli were presented to the right lower lip (all 8 visits) as well as right and left index fingers (visits 3-8) and fifth digits (visits 4-8). In addition, left and right-hand motor responses were also recorded for left index finger and right thumb (visit 8 only).During the acute recovery phase (visits 3 and 4), somatosensory responses of the digits were observed to be significantly larger and more phasic (i.e., smoother) than controls. Subsequent measures showed that digit responses maintain this atypical response profile (evoked-response magnitudes typically exceed 1 picoTesla). Orthotopic somatosensory localization of the lip, D2, and D5 was preserved. Motor beta-band desynchrony was age-typical in localization and response magnitude; however, the motor gamma-band response was significantly larger than that observed in a reference population.These novel findings show that the restoration of somatosensory input of the hands resulted in persistent and atypically large cortical responses to digit stimulation, which remain atypically large at 6 years post-transplant; there is no known perceptual correlate, and no reports of phantom pain. Normal somatosensory organization of the lip, D2, and D5 representation remain stable following post-recovery reorganization of the lip's somatosensory response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Magnetoencephalography (MEG) is particularly well-suited to the study of human motor cortex oscillatory rhythms and motor control. However, the motor tasks studied to date are largely overly simplistic. This study describes a new approach: a novel event-based simulated drive made operational via MEG compatible driving simulator hardware, paired with differential beamformer methods to characterize the neural correlates of realistic, complex motor activity. We scanned 23 healthy individuals aged 16-23 years (mean age = 19.5, SD = 2.5; 18 males and 5 females, all right-handed) who completed a custom-built repeated trials driving scenario. MEG data were recorded with a 275-channel CTF, and a volumetric magnetic resonance imaging scan was used for MEG source localization. To validate this paradigm, we hypothesized that pedal-use would elicit expected modulation of primary motor responses beta-event-related desynchronization (B-ERD) and movement-related gamma synchrony (MRGS). To confirm the added utility of this paradigm, we hypothesized that the driving task could also probe frontal cognitive control responses (specifically, frontal midline theta [FMT]). Three of 23 participants were removed due to excess head motion (>1.5 cm/trial), confirming feasibility. Nonparametric group analysis revealed significant regions of pedal-use related B-ERD activity (at left precentral foot area, as well as bilateral superior parietal lobe: p < .01 corrected), MRGS (at medial precentral gyrus: p < .01 corrected), and FMT band activity sustained around planned braking (at bilateral superior frontal gyrus: p < .01 corrected). This paradigm overcomes the limits of previous efforts by allowing for characterization of the neural correlates of realistic, complex motor activity in terms of brain regions, frequency bands and their dynamic temporal interplay., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies., Methods: Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1-17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study., Results: As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome., Conclusions: There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions., (© 2023. The Author(s).)

Epilepsy is a highly heterogeneous neurological disorder with variable etiology, manifestation, and response to treatment. It is imperative that new models of epileptiform brain activity account for this variability, to identify individual needs and allow clinicians to curate personalized care. Here, we use a hidden Markov model (HMM) to create a unique statistical model of interictal brain activity for 10 pediatric patients. We use magnetoencephalography (MEG) data acquired as part of standard clinical care for patients at the Children's Hospital of Philadelphia. These data are routinely analyzed using excess kurtosis mapping (EKM); however, as cases become more complex (extreme multifocal and/or polymorphic activity), they become harder to interpret with EKM. We assessed the performance of the HMM against EKM for three patient groups, with increasingly complicated presentation. The difference in localization of epileptogenic foci for the two methods was 7 ± 2 mm (mean ± SD over all 10 patients); and 94% ± 13% of EKM temporal markers were matched by an HMM state visit. The HMM localizes epileptogenic areas (in agreement with EKM) and provides additional information about the relationship between those areas. A key advantage over current methods is that the HMM is a data-driven model, so the output is tuned to each individual. Finally, the model output is intuitive, allowing a user (clinician) to review the result and manually select the HMM epileptiform state, offering multiple advantages over previous methods and allowing for broader implementation of MEG epileptiform analysis in surgical decision-making for patients with intractable epilepsy., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Magnetoencephalography, the extracranial detection of tiny magnetic fields emanating from intracranial electrical activity of neurons, and its source modeling relation, magnetic source imaging, represent a powerful functional neuroimaging technique, able to detect and localize both spontaneous and evoked activity of the brain in health and disease. Recent years have seen an increased utilization of this technique for both clinical practice and research, in the United States and worldwide. This report summarizes current thinking, presents recommendations for clinical implementation, and offers an outlook for emerging new clinical indications., (© 2022 by American Journal of Neuroradiology.)

Introduction: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA., Methods: 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers., Discussion: Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression., Clinical Trial Registration: ClinicalTrails.gov Identifier: NCT04349514., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: R.E. and S.Z. are employed by Takeda Pharmaceutical Company Ltd with both authors receiving salary and S.Z. holds stocks in the company. A.S. was employed by Takeda Pharmaceutical Company Ltd at the time of his contribution to the TRACK-FA project. Takeda Pharmaceutical Company Ltd remains committed to FRDA research and will help develop translational tools to monitor patient disease and share with the FRDA community. T.S. and B.Y. are both employees of PTC Therapeutics. D.L. is a grant recipient from the National Institute of Health (NIH), Muscular Dystrophy Association (MDA), Friedreich’s Ataxia Research Alliance (FARA), Reata Pharmaceuticals Inc, Retrotope Inc, Voyager Therapeutics, Novartis Gene Therapies, Audentes Therapeutics (Astellas Gene Therapies) and Minoryx Therapeutics S.L. T.P.L.R. has equity interest in PRISM Clinical Imaging and Proteus Neurodynamics and consulting/advisory board engagement with CTF MEG International Services LP, Ricoh Company Ltd, Spago Nanomedical AB, Avexis (Novartis Gene Therapies) and Acadia Pharmaceuticals Inc. P.G.H. is a grant recipient from the Friedreich’s Ataxia Research Alliance (FARA), GoFAR, Ataxia UK, the Bob Allison Ataxia Research Centre, and the National Institute of Health (NIH). CMRR is supported by NIH grants P41EB027061 and P30NS076408. P.G.H. reports grants from Minoryx Therapeutics for activities outside this study. M.P. and R.J. and M.L. are employed by IXICO plc, ML is a shareholder for IXICO plc. M.C.F. is a grant recipient from PTC Therapeutics and has taken part in advisory board for PTC Therapeutics and Avexis (Novartis Gene Therapies). T.R. is a grant recipient from the Friedreich’s Ataxia Research Alliance (FARA). C.L. is a research grant recipient from the Friedreich’s Ataxia Research Alliance (FARA), GoFAR, Ataxia UK, the Bob Allison Ataxia Research Center, and National Institute of Health (NIH) grants P41. EB027061 and P30 NS076408. C.L. reports research grants from Minoryx Therapeutics and Biogen Inc. for activities outside this study. S.S. is a broad member of the Research Advisory Board for National Ataxia Foundation (USA), a research grant recipient from the Friedreich’s Ataxia Research Alliance (FARA), Wyck Foundation, National Ataxia Foundation, Muscular Dystrophy Association (MDA), National Institute of Health (NIH), FDA and receives industry support from Reata Pharmaceutical Inc, Retrotope Inc, PTC Therapeutics, Biohaven Pharmaceuticals, Avidity Biosciences Inc, and Strides Pharma Science Limited. M.L.K. holds shares in Novartis Gene Therapies. K.R. has received grants from the German Federal Ministry of Education and Research (BMBF 01GQ1402, 01DN18022), the German Research Foundation (IRTG 2150, ZUK32/1), Alzheimer Forschung Initiative e.V. (AFI 13812, NL-18002CB) and honoraria for presentations or advisory boards from Biogen and Roche. J.F. is employed by the Friedreich’s Ataxia Research Alliance (FARA) and receives a salary from this institution. L.C. is a research grant recipient from the Friedreich Ataxia Research Alliance (FARA), Ataxia UK, Medical Research Future Fund and is funded by a Medical Research Futures Fund Next Generation Career Development Fellowship., (Copyright: © 2022 Georgiou-Karistianis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Infant and young child electrophysiology studies have provided information regarding the maturation of face-encoding neural processes. A limitation of previous research is that very few studies have examined face-encoding processes in children 12-48 months of age, a developmental period characterized by rapid changes in the ability to encode facial information. The present study sought to fill this gap in the literature via a longitudinal study examining the maturation of a primary node in the face-encoding network-the left and right fusiform gyrus (FFG). Whole-brain magnetoencephalography (MEG) data were obtained from 25 infants with typical development at 4-12 months, and with follow-up MEG exams every ∼12 months until 3-4 years old. Children were presented with color images of Face stimuli and visual noise images (matched on spatial frequency, color distribution, and outer contour) that served as Non-Face stimuli. Using distributed source modeling, left and right face-sensitive FFG evoked waveforms were obtained from each child at each visit, with face-sensitive activity identified via examining the difference between the Non-Face and Face FFG timecourses. Before 24 months of age (Visits 1 and 2) the face-sensitive FFG M290 response was the dominant response, observed in the left and right FFG ∼250-450 ms post-stimulus. By 3-4 years old (Visit 4), the left and right face-sensitive FFG response occurred at a latency consistent with a face-sensitive M170 response ∼100-250 ms post-stimulus. Face-sensitive left and right FFG peak latencies decreased as a function of age (with age explaining greater than 70% of the variance in face-sensitive FFG latency), and with an adult-like FFG latency observed at 3-4 years old. Study findings thus showed face-sensitive FFG maturational changes across the first 4 years of life. Whereas a face-sensitive M290 response was observed under 2 years of age, by 3-4 years old, an adult-like face-sensitive M170 response was observed bilaterally. Future studies evaluating the maturation of face-sensitive FFG activity in infants at risk for neurodevelopmental disorders are of interest, with the present findings suggesting age-specific face-sensitive neural markers of a priori interest., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Allison, Green, Kuschner, Liu, Kim, Slinger, Mol, Chiang, Bloy, Roberts and Edgar.)

CDKL5 deficiency disorder is a debilitating developmental and epileptic encephalopathy for which no targeted treatment exists. A number of promising therapeutics are under development for CDKL5 deficiency disorder but a lack of validated biomarkers of brain function and clinical severity may limit the ability to objectively assess the efficacy of new treatments as they become available. To address this need, the current study quantified electrophysiological measures in individuals with CDKL5 deficiency disorder and the association between these parameters and clinical severity. Visual and auditory evoked potentials, as well as resting EEG, were acquired across 5 clinical sites from 26 individuals with CDKL5 deficiency disorder. Evoked potential and quantitative EEG features were calculated and compared with typically developing individuals in an age- and sex-matched cohort. Baseline and Year 1 data, when available, were analysed and the repeatability of the results was tested. Two clinician-completed severity scales were used for evaluating the clinical relevance of the electrophysiological parameters. Group-level comparisons revealed reduced visual evoked potential amplitude in CDKL5 deficiency disorder individuals versus typically developing individuals. There were no group differences in the latency of the visual evoked potentials or in the latency or amplitude of the auditory evoked potentials. Within the CDKL5 deficiency disorder group, auditory evoked potential amplitude correlated with disease severity at baseline as well as Year 1. Multiple quantitative EEG features differed between CDKL5 deficiency disorder and typically developing participants, including amplitude standard deviation, 1/f slope and global delta, theta, alpha and beta power. Several quantitative EEG features correlated with clinical severity, including amplitude skewness, theta/delta ratio and alpha/delta ratio. The theta/delta ratio was the overall strongest predictor of severity and also among the most repeatable qEEG measures from baseline to Year 1. Together, the present findings point to the utility of evoked potentials and quantitative EEG parameters as objective measures of brain function and disease severity in future clinical trials for CDKL5 deficiency disorder. The results also underscore the utility of the current methods, which could be similarly applied to the identification and validation of electrophysiological biomarkers of brain function for other developmental encephalopathies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: At rest, 8 to 12 Hz alpha rhythms are the dominant rhythm in the brain, with a common peak alpha frequency (PAF = the frequency at which alpha generators show maximum power) observed across brain regions. Although a common PAF across brain regions should result in high between-region connectivity, especially connectivity measures assessing the phase-similarity between alpha generators, high inter-regional alpha connectivity has not been observed. The present study was conducted as an initial step toward identifying mechanisms that allow brain regions to maintain functional independence in the presence of a common PAF., Methods: MEG data were obtained from 16 healthy control male adults (mean age = 24 years; range 21 to 30 years). A task requiring participants to alternate between a 10 s eyes-closed condition and a 5 s eyes-open condition was used to drive parietal-occipital alpha generators, with the 10 s eyes-closed condition eliciting large-amplitude alpha activity and thus providing alpha measures with good signal-to-noise ratio for source localization. Alpha source-space measures were obtained using Vector-based Spatial-Temporal Analysis using L1-minimum-norm. In each participant, the four strongest parietal-occipital alpha generators were identified. Connectivity between sources was assessed via a measure of phase-based connectivity called inter-site phase clustering (ISPC)., Results: Intra-class correlations (ICC) showed very high similarity in the average PAF (=computed using all eyes-closed data) between the four alpha sources (ICC single measure = 0.88, p < 0.001). Despite a common average PAF, across participants, significant ISPC was often observed no more than that expected by chance. Examination of the alpha time course data indicated that low ISPC was often due to instantaneous changes in alpha phase (phase slips). ISPC analyses removing data with phase slips indicated that low ISPC was also due to slight continuous changes in the alpha frequency, with frequency drift more likely in non-significant than significant ISPC trials., Conclusions: The present exploratory effort suggested two processes underlying the lack of observed inter-regional alpha phase coherence that may help maintain regional functional independence even in the presence of a common PAF. In particular, although the alpha generators were observed to oscillate at the same rate on average, across time each alpha generator oscillated a little slower or faster, and about every one and a half seconds an alpha generator abruptly lost the beat. Because of this, functional independence among alpha generators (and thus brain regions) was the rule rather than the exception. Studies replicating these processes that allow brain regions to maintain functional independence, using different source localization methods and in different conditions (e.g., a true resting state), are warranted., Impact Statement: Using source localization to measure parietal-occipital alpha generator activity, two properties that limit between-region alpha functional connectivity are proposed. In particular, a model of alpha generator activity is offered where via transient phase slips occurring approximately every 1.5 s, as well as slight non-stationarity in the alpha frequency, brain regions retain a common alpha frequency while also maintaining regional identity and presumably functionality. Findings also suggest novel markers for use in studies examining changes in alpha activity across maturation as well as in studies examining alpha activity in patient populations where alpha abnormalities have been reported., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Associations between age, resting-state (RS) peak-alpha-frequency (PAF = frequency showing largest amplitude alpha activity), and thalamic volume (thalamus thought to modulate alpha activity) were examined to understand differences in RS alpha activity between children with autism spectrum disorder (ASD) and typically-developing children (TDC) noted in prior studies. RS MEG and structural-MRI data were obtained from 51 ASD and 70 TDC 6- to 18-year-old males. PAF and thalamic volume maturation were observed in TDC but not ASD. Although PAF was associated with right thalamic volume in TDC (R 2  = 0.12, p = 0.01) but not ASD (R 2  = 0.01, p = 0.35), this group difference was not large enough to reach significance. Findings thus showed unusual maturation of brain function and structure in ASD as well as an across-group thalamic contribution to alpha rhythms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Prevailing theories of the neural basis of at least a subset of individuals with autism spectrum disorder (ASD) include an imbalance of excitatory and inhibitory neurotransmission. These circuitry imbalances are commonly probed in adults using auditory steady-state responses (ASSR, driven at 40 Hz) to elicit coherent electrophysiological responses (EEG/MEG) from intact circuitry. Challenges to the ASSR methodology occur during development, where the optimal ASSR driving frequency may be unknown. An alternative approach (more agnostic to driving frequency) is the amplitude-modulated (AM) sweep in which the amplitude of a tone (with carrier frequency 500 Hz) is modulated as a sweep from 10 to 100 Hz over the course of ∼15 s. Phase synchrony of evoked responses, measured via intra-trial coherence, is recorded (by EEG or MEG) as a function of frequency. We applied such AM sweep stimuli bilaterally to 40 typically developing and 80 children with ASD, aged 6-18 years. Diagnoses were confirmed by DSM-5 criteria as well as autism diagnostic observation schedule (ADOS) observational assessment. Stimuli were presented binaurally during MEG recording and consisted of 20 AM swept stimuli (500 Hz carrier; sweep 10-100 Hz up and down) with a duration of ∼30 s each. Peak intra-trial coherence values and peak response frequencies of source modeled responses (auditory cortex) were examined. First, the phase synchrony or inter-trial coherence (ITC) of the ASSR is diminished in ASD; second, hemispheric bias in the ASSR, observed in typical development (TD), is maintained in ASD, and third, that the frequency at which the peak response is obtained varies on an individual basis, in part dependent on age, and with altered developmental trajectories in ASD vs. TD. Finally, there appears an association between auditory steady-state phase synchrony (taken as a proxy of neuronal circuitry integrity) and clinical assessment of language ability/impairment. We concluded that (1) the AM sweep stimulus provides a mechanism for probing ASSR in an unbiased fashion, during developmental maturation of peak response frequency, (2) peak frequencies vary, in part due to developmental age, and importantly, (3) ITC at this peak frequency is diminished in ASD, with the degree of ITC disturbance related to clinically assessed language impairment., Competing Interests: TR declares equity in Prism Clinical Imaging and Proteus Neurodynamics. He serves as a consultant/medical advisory board member for CTF, Ricoh, Spago Nanomedicine, Avexis and Acadia Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Roberts, Bloy, Liu, Ku, Blaskey and Jackel.)

Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B 0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites., Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC)., Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI., Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed., Competing Interests: Declaration of Competing Interest Jack J. Miller would like to acknowledge the support of a Novo Nordisk Research Fellowship run in conjunction with the University of Oxford. Francisco Reyes-Madrigal has served as a speaker for Janssen (Johnson & Johnson) and AstraZeneca. Marc Thioux and Pim van Dijk were supported by The Netherlands Organization for Health Research and Development (ZonMW) and the Dorhout Mees Foundation. All other authors have no conflict of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

This paper reviews a candidate biomarker for ASD, the M50 auditory evoked response component, detected by magnetoencephalography (MEG) and presents a position on the roles and opportunities for such a biomarker, as well as converging evidence from allied imaging techniques (magnetic resonance imaging, MRI and spectroscopy, MRS). Data is presented on prolonged M50 latencies in ASD as well as extension to include children with ASD with significant language and cognitive impairments in whom M50 latency delays are exacerbated. Modeling of the M50 latency by consideration of the properties of auditory pathway white matter is shown to be successful in typical development but challenged by heterogeneity in ASD; this, however, is capitalized upon to identify a distinct subpopulation of children with ASD whose M50 latencies lie well outside the range of values predictable from the typically developing model. Interestingly, this subpopulation is characterized by low levels of the inhibitory neurotransmitter GABA. Following from this, we discuss a potential use of the M50 latency in indicating "target engagement" acutely with administration of a GABA-B agonist, potentially distinguishing "responders" from "non-responders" with the implication of optimizing inclusion for clinical trials of such agents. Implications for future application, including potential evaluation of infants with genetic risk factors, are discussed. As such, the broad scope of potential of a representative candidate biological marker, the M50 latency, is introduced along with potential future applications.This paper outlines a strategy for understanding brain dysfunction in individuals with intellectual and developmental disabilities (IDD). It is proposed that a multimodal approach (collection of brain structure, chemistry, and neuronal functional data) will identify IDD subpopulations who share a common disease pathway, and thus identify individuals with IDD who might ultimately benefit from specific treatments. After briefly demonstrating the need and potential for scope, examples from studies examining brain function and structure in children with autism spectrum disorder (ASD) illustrate how measures of brain neuronal function (from magnetoencephalography, MEG), brain structure (from magnetic resonance imaging, MRI, especially diffusion MRI), and brain chemistry (MR spectroscopy) can help us better understand the heterogeneity in ASD and form the basis of multivariate biological markers (biomarkers) useable to define clinical subpopulations. Similar approaches can be applied to understand brain dysfunction in neurodevelopmental disorders (NDD) in general. In large part, this paper represents our endeavors as part of the CHOP/Penn NICHD-funded intellectual and developmental disabilities research center (IDDRC) over the past decade., (© 2021. The Author(s).)

Background: 47,XYY syndrome (XYY) is a male sex chromosome disorder where subjects have one X chromosome and two copies of the Y chromosome. XYY is associated with a physical phenotype and carries increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Imbalance of excitation and inhibition has been proposed as a putative biological basis of disorders such as ASD [1-3] and several studies have reported atypical brain γ-aminobutyric acid (GABA) levels in this population. Given the male preponderance in the prevalence of ASD, the unique presence of the Y chromosome in males leads to the intriguing possibility of investigating boys with XYY syndrome as a model of excess Y-chromosome genes., Method: In this study, we investigated the associations of genotype and clinical phenotype with levels of GABA, estimated by regionally localized edited magnetic resonance spectroscopy in boys with 47, XYY syndrome compared to age-matched typically developing (XY) peers., Results: Overall, we observed a decrease in GABA levels in XYY vs. XY, which appeared more significant in the left compared to the right hemisphere. There was no additional significant modulation of GABA levels in XYY according to presence/absence of ASD diagnosis. Interestingly, a positive correlation between bilateral GABA levels and testosterone levels was observed in pubescent XY boys that was not observed in XYY., Conclusion: The inhibitory neurotransmitter GABA appears to be reduced in boys with 47,XYY, especially in the left hemisphere. Further, the typical association between GABA and testosterone levels, observed in older typically developing control boys was not evident in boys with 47,XYY., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of the current study was to evaluate the utility of evoked potentials as a biomarker of cortical function in Rett syndrome (RTT). As a number of disease-modifying therapeutics are currently under development, there is a pressing need for biomarkers to objectively and precisely assess the effectiveness of these treatments., Method: Yearly visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were acquired from individuals with RTT, aged 2 to 37 years, and control participants across 5 sites as part of the Rett Syndrome and Related Disorders Natural History Study. Baseline and year 1 data, when available, were analyzed and the repeatability of the results was tested. Two syndrome-specific measures from the Natural History Study were used for evaluating the clinical relevance of the VEP and AEP parameters., Results: At the baseline study, group level comparisons revealed reduced VEP and AEP amplitude in RTT compared to control participants. Further analyses within the RTT group indicated that this reduction was associated with RTT-related symptoms, with greater severity associated with lower VEP and AEP amplitude. In participants with RTT, VEP and AEP amplitude was also negatively associated with age. Year 1 follow-up data analyses yielded similar findings and evidence of repeatability of EPs at the individual level., Interpretation: The present findings indicate the promise of evoked potentials (EPs) as an objective measure of disease severity in individuals with RTT. Our multisite approach demonstrates potential research and clinical applications to provide unbiased assessment of disease staging, prognosis, and response to therapy. ANN NEUROL 2021;89:790-802., (© 2021 American Neurological Association.)

Little is known about the neural processes associated with attending to social stimuli during infancy and toddlerhood. Using infant magnetoencephalography (MEG), fusiform gyrus (FFG) activity while processing Face and Non-Face stimuli was examined in 46 typically developing infants 3 to 24 months old (28 males). Several findings indicated FFG maturation throughout the first two years of life. First, right FFG responses to Face stimuli decreased as a function of age. Second, hemispheric specialization to the face stimuli developed somewhat slowly, with earlier right than left FFG peak activity most evident after 1 year of age. Right FFG activity to Face stimuli was of clinical interest, with an earlier right FFG response associated with better performance on tests assessing social and cognitive ability. Building on the above, clinical studies examining maturational change in FFG activity (e.g., lateralization and speed) in infants at-risk for childhood disorders associated with social deficits are of interest to identify atypical FFG maturation before a formal diagnosis is possible., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Neuroimaging research on individuals who have autism spectrum disorder (ASD) has historically been limited primarily to those with age-appropriate cognitive and language performance. Children with limited abilities are frequently excluded from such neuroscience research given anticipated barriers like tolerating the loud sounds associated with magnetic resonance imaging and remaining still during data collection. To better understand brain function across the full range of ASD there is a need to (1) include individuals with limited cognitive and language performance in neuroimaging research (non-sedated, awake) and (2) improve data quality across the performance range. The purpose of this study was to develop, implement, and test the feasibility of a clinical/behavioral and technical protocol for obtaining magnetoencephalography (MEG) data. Participants were 38 children with ASD (8-12 years) meeting the study definition of minimally verbal/nonverbal language. MEG data were obtained during a passive pure-tone auditory task., Results: Based on stakeholder feedback, the MEG Protocol for Low-language/cognitive Ability Neuroimaging (MEG-PLAN) was developed, integrating clinical/behavioral and technical components to be implemented by an interdisciplinary team (clinicians, behavior specialists, scientists, and technologists). Using MEG-PLAN, a 74% success rate was achieved for acquiring MEG data, with a 71% success rate for evaluable and analyzable data. Exploratory analyses suggested nonverbal IQ and adaptive skills were related to reaching the point of acquirable data. No differences in group characteristics were observed between those with acquirable versus evaluable/analyzable data. Examination of data quality (evaluable trial count) was acceptable. Moreover, results were reproducible, with high intraclass correlation coefficients for pure-tone auditory latency., Conclusions: Children who have ASD who are minimally verbal/nonverbal, and often have co-occurring cognitive impairments, can be effectively and comfortably supported to complete an electrophysiological exam that yields valid and reproducible results. MEG-PLAN is a protocol that can be disseminated and implemented across research teams and adapted across technologies and neurodevelopmental disorders to collect electrophysiology and neuroimaging data in previously understudied groups of individuals.

Functional brain markers that can inform research on brain abnormalities, and especially those ready to facilitate clinical work on such abnormalities, will need to show not only considerable sensitivity and specificity but enough consistency with respect to developmental course that their validity in individual cases can be trusted. A challenge to establishing such markers may be individual differences in developmental course. The present study examined auditory cortex activity in children at an age when developmental changes to the auditory cortex 50 ms (M50) and 100 ms (M100) components are prominent to better understand the use of auditory markers in pediatric clinical research. MEG auditory encoding measures (auditory evoked fields in response to pure tone stimuli) were obtained from 15 typically developing children 6-8 years old, with measures repeated 18 and 36 months after the initial exam. MEG analyses were conducted in source space (i.e., brain location), with M50 and M100 sources identified in left and right primary/secondary auditory cortex (Heschl's gyrus). A left and right M50 response was observed at all times (Time 1, Time 2, Time 3), with M50 latency (collapsing across hemisphere) at Time 3 (77 ms) 10 ms earlier than Time 1 (87 ms; p < 0.001) and with M50 responses on average (collapsing across time) 5 ms earlier in the right (80 ms) than left hemisphere (85 ms; p < 0.05). In the majority of children, however, M50 latency changes were not constant across the three-year period; for example, whereas in some children a ~10 ms latency reduction was observed from Time 1 to Time 2, in other children a ~10 ms latency reduction was observed from Time 2 to Time 3. M100 responses were defined by a significant "peak" of detected power with magnetic field topography opposite M50 and occurring 50-100 ms later than the M50. Although M100s were observed in a few children at Time 1 and Time 2 (and more often in the right than left hemisphere), M100s were not observed in the majority of children except in the right hemisphere at Time 3. In sum, longitudinal findings showed large between- and within-subject variability in rate of change as well as time to reach neural developmental milestones (e.g., presence of a detectable M100 response). Findings also demonstrated the need to examine whole-brain activity, given hemisphere differences in the rate of auditory cortex maturation. Pediatric research will need to take such normal variability into account when seeking clinical auditory markers., (Copyright © 2020 Edgar, Blaskey, Green, Konka, Shen, Dipiero, Berman, Bloy, Liu, McBride, Ku, Kuschner, Airey, Kim, Franzen, Miller and Roberts.)

Background: Individuals with either deletion or duplication of the BP4-BP5 segment of chromosome 16p11.2 have varied behavioral phenotypes that may include autistic features, mild to moderate intellectual disability, and/or language impairment. However, the neurophysiological correlates of auditory language discrimination processing in individuals with 16p11.2 deletion and 16p11.2 duplication have not been investigated., Methods: Magnetoencephalography was used to measure magnetic mismatch fields (MMFs) arising from the left and right superior temporal gyrus during an auditory oddball paradigm with vowel stimuli (/a/ and /u/) in children and adolescents with 16p11.2 deletion or 16p11.2 duplication and in typically developing peers. One hundred twenty-eight participants ranging from 7 to 17 years of age were included in the final analysis (typically developing: n = 61, 12.08 ± 2.50 years of age; 16p11.2 deletion: n = 45, 11.28 ± 2.51 years of age; and 16p11.2 duplication: n = 22, 10.73 ± 2.49 years of age)., Results: Delayed MMF latencies were found in both 16p11.2 deletion and 16p11.2 duplication groups compared with typically developing subjects. In addition, these delayed MMF latencies were associated with language and cognitive ability, with prolonged latency predicting greater impairment., Conclusions: Our findings suggest that auditory MMF response delays are associated with clinical severity of language and cognitive impairment in individuals with either 16p11.2 deletion or 16p11.2 duplication, indicating a correlate of their shared/overlapping behavioral phenotype (and not a correlate of gene dosage)., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

This multimodal imaging study used magnetoencephalography, diffusion magnetic resonance imaging (MRI), and gamma-aminobutyric acid (GABA) magnetic resonance spectroscopy (MRS) to identify and contrast the multiple physiological mechanisms associated with auditory processing efficiency in typically developing (TD) children and children with autism spectrum disorder (ASD). Efficient transmission of auditory input between the ear and auditory cortex is necessary for rapid encoding of auditory sensory information. It was hypothesized that the M50 auditory evoked response latency would be modulated by white matter microstructure (indexed by diffusion MRI) and by tonic inhibition (indexed by GABA MRS). Participants were 77 children diagnosed with ASD and 40 TD controls aged 7-17 years. A model of M50 latency with auditory radiation fractional anisotropy and age as independent variables was able to predict 52% of M50 latency variance in TD children, but only 12% of variance in ASD. The ASD group exhibited altered patterns of M50 latency modulation characterized by both higher variance and deviation from the expected structure-function relationship established with the TD group. The TD M50 latency model was used to identify a subpopulation of ASD who are significant "outliers" to the TD model. The ASD outlier group exhibited unexpectedly long M50 latencies in conjunction with significantly lower GABA levels. These findings indicate the dependence of electrophysiologic sensory response latency on underlying microstructure (white matter) and neurochemistry (synaptic activity). This study demonstrates the use of biologically based measures to stratify ASD according to their brain-level "building blocks" as an alternative to their behavioral phenotype. LAY SUMMARY: Children with ASD often have a slower brain response when hearing sounds. This study used multiple brain imaging techniques to examine the structural and neurochemical factors which control the brain's response time to auditory tones in children with ASD and TD children. The relationship between brain imaging measures and brain response time was also used to identify ASD subgroups. Autism Res 2020, 13: 1730-1745. © 2020 International Society for Autism Research and Wiley Periodicals LLC., (© 2020 International Society for Autism Research and Wiley Periodicals LLC.)

An additional Y chromosome occurs in ~1 in 1,000 males, resulting in the karyotype 47,XYY. The phenotype includes tall stature, hypotonia, neuropsychiatric comorbidities, and an increased risk of infertility in adulthood. Little is known about testicular function in childhood and adolescence in 47,XYY. This cross-sectional study aimed to assess testicular function serum biomarkers, including total testosterone, inhibin B, and anti-mullerian hormone (AMH), in 82 boys with XYY (11.3 ± 3.8 years) compared with 66 male controls (11.6 ± 3.8 years). The association of testicular hormones with physical features, neuropsychological phenotype, and magnetoencephalography (MEG) was assessed with multiple linear regression models. Results indicate males with XYY have significantly lower inhibin B (median 84 pg/ml vs. 109 pg/ml, p = .004) and higher AMH (median 41 ng/ml vs. 29 ng/ml, p = .011); however, testosterone, testicular volume, and stretched penile length were not different from controls. In the exploratory analysis of relationships between hormone concentrations and phenotypic assessments, higher inhibin B concentrations were positively correlated with lower BMI and better cognitive, academic, and behavioral outcomes in the XYY group. Testosterone concentrations were positively associated with better behavioral outcomes in boys with XYY. Higher testosterone and inhibin B concentrations were also associated with shorter auditory latencies measured using magnetoencephalography (MEG) in XYY. With a few exceptions, testicular hormones were not associated with phenotypic outcomes in controls. In conclusion, there is evidence of subtle impaired testicular function in boys with XYY and a newly described relationship between measures of testicular function and some aspects of the XYY phenotype., (© 2020 Wiley Periodicals LLC.)

Background MRI performed at 3.0 T offers greater signal-to-noise ratio and better spatial resolution than does MRI performed at 1.5 T; however, for fetal MRI, there are concerns about the potential for greater radiofrequency energy administered to the fetus at 3.0-T MRI. Purpose To compare the specific absorption rate (SAR) and specific energy dose (SED) of fetal MRI at 1.5 and 3.0 T. Materials and Methods In this retrospective study, all fetal MRI examinations performed with 1.5- and 3.0-T scanners at one institution between July 2012 and October 2016 were evaluated. Two-dimensional (2D) and three-dimensional (3D) steady-state free precession (SSFP), single-shot fast spin-echo, 2D and 3D T1-weighted spoiled gradient-echo (SPGR), and echo-planar imaging sequences were performed. SAR, SED, accumulated SED, and acquisition time were retrieved from the Digital Imaging and Communications in Medicine header. Data are presented as mean ± standard deviation. Two one-sided tests with equivalence bounds of 0.5 (Cohen d effect size) were performed, with statistical equivalence considered at P < .05. Results A total of 2952 pregnant women were evaluated. Mean maternal age was 30 years ± 6 (age range, 12-49 years), mean gestational age was 24 weeks ± 6 (range, 17-40 weeks). A total of 3247 fetal MRI scans were included, with 2784 (86%) obtained at 1.5 T and 463 (14%) obtained at 3.0 T. In total, 93 764 sequences were performed, with 81 535 (87%) performed at 1.5 T and 12 229 (13%) performed at 3.0 T. When comparing 1.5- with 3.0-T MRI sequences, mean SAR (1.09 W/kg ± 0.69 vs 1.14 W/kg ± 0.61), mean SED (33 J/kg ± 27 vs 38 J/kg ± 26), and mean accumulated SED (965 J/kg ± 408 vs 996 J/kg ± 366, P < .001) were equivalent. Conclusion Fetal 1.5- and 3.0-T MRI examinations were found to have equivalent energy metrics in most cases. The 3.0-T sequences, such as two-dimensional T1-weighted spoiled gradient-echo and three-dimensional steady-state free precession, may require modification to keep the energy delivered to the patient as low as possible. © RSNA, 2020 Online supplemental material is available for this article.

Rett syndrome is a debilitating neurodevelopmental disorder for which no disease-modifying treatment is available. Fortunately, advances in our understanding of the genetics and pathophysiology of Rett syndrome has led to the development of promising new therapeutics for the condition. Several of these therapeutics are currently being tested in clinical trials with others likely to progress to clinical trials in the coming years. The failure of recent clinical trials for Rett syndrome and other neurodevelopmental disorders has highlighted the need for electrophysiological or other objective biological markers of treatment response to support the success of clinical trials moving forward. The purpose of this review is to describe the existing studies of electroencephalography (EEG) and evoked potentials (EPs) in Rett syndrome and discuss the open questions that must be addressed before the field can adopt these measures as surrogate endpoints in clinical trials. In addition to summarizing the human work on Rett syndrome, we also describe relevant studies with animal models and the limited research that has been carried out on Rett-related disorders, particularly methyl-CpG binding protein 2 (MECP2) duplication syndrome, CDKL5 deficiency disorder, and FOXG1 disorder., (Copyright © 2020 Saby, Peters, Roberts, Nelson and Marsh.)

Magnetoencephalography (MEG) research indicates differences in neural brain measures in children with autism spectrum disorder (ASD) compared to typically developing (TD) children. As reviewed here, resting-state MEG exams are of interest as well as MEG paradigms that assess neural function across domains (e.g., auditory, resting state). To date, MEG research has primarily focused on group-level differences. Research is needed to explore whether MEG measures can predict, at the individual level, ASD diagnosis, prognosis (future severity), and response to therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)