Social challenges, autism spectrum disorder, and attention deficit/hyperactivity disorder in youth with neurofibromatosis type I.

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 (Mage = 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- 2nd 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.

Association of EEG Background With Diffusion-Weighted Magnetic Resonance Neuroimaging and Short-Term Outcomes After Pediatric Cardiac Arrest.

BACKGROUND AND OBJECTIVES: EEG and MRI features are independently associated with pediatric cardiac arrest (CA) outcomes, but it is unclear whether their combination improves outcome prediction. We aimed to assess the association of early EEG background category with MRI ischemia after pediatric CA and determine whether addition of MRI ischemia to EEG background features and clinical variables improves short-term outcome prediction. METHODS: This was a single-center retrospective cohort study of pediatric CA with EEG initiated ≤24 hours and MRI obtained ≤7 days of return of spontaneous circulation. Initial EEG background was categorized as normal, slow/disorganized, discontinuous/burst-suppression, or attenuated-featureless. MRI ischemia was defined as percentage of brain tissue with apparent diffusion coefficient (ADC) <650 × 10-6 mm2/s and categorized as high (≥10%) or low (<10%). Outcomes were mortality and unfavorable neurologic outcome (Pediatric Cerebral Performance Category increase ≥1 from baseline resulting in ICU discharge score ≥3). The Kruskal-Wallis test evaluated the association of EEG with MRI. Area under the receiver operating characteristic (AUROC) curve evaluated predictive accuracy. Logistic regression and likelihood ratio tests assessed multivariable outcome prediction. RESULTS: We evaluated 90 individuals. EEG background was normal in 16 (18%), slow/disorganized in 42 (47%), discontinuous/burst-suppressed in 12 (13%), and attenuated-featureless in 20 (22%) individuals. The median percentage of MRI ischemia was 5% (interquartile range 1-18); 32 (36%) individuals had high MRI ischemia burden. Twenty-eight (31%) individuals died, and 58 (64%) had unfavorable neurologic outcome. Worse EEG background category was associated with more MRI ischemia (p < 0.001). The combination of EEG background and MRI ischemia burden had higher predictive accuracy than EEG alone (AUROC: mortality: 0.92 vs 0.87, p = 0.03) or MRI alone (AUROC: mortality: 0.92 vs 0.84, p = 0.02; unfavorable: 0.83 vs 0.73, p < 0.01). Addition of percentage of MRI ischemia to clinical variables and EEG background category improved prediction for mortality (χ2 = 19.1, p < 0.001) and unfavorable neurologic outcome (χ2 = 4.8, p = 0.03) and achieved high predictive accuracy (AUROC: mortality: 0.97; unfavorable: 0.92). DISCUSSION: Early EEG background category was associated with MRI ischemia after pediatric CA. Combining EEG and MRI data yielded higher outcome predictive accuracy than either modality alone. The addition of MRI ischemia to clinical variables and EEG background improved short-term outcome prediction.

Association between ASL MRI-derived cerebral blood flow and outcomes after pediatric cardiac arrest.

AIM: Cerebral blood flow (CBF) is dysregulated after cardiac arrest. It is unknown if post-arrest CBF is associated with outcome. We aimed to determine the association of CBF derived from arterial spin labelling (ASL) MRI with outcome after pediatric cardiac arrest. METHODS: Retrospective observational study of patients ≤18 years who had a clinically obtained brain MRI within 7 days of cardiac arrest between June 2005 and December 2019. Primary outcome was unfavorable neurologic status: change in Pediatric Cerebral Performance Category (PCPC) ≥1 from pre-arrest that resulted in hospital discharge PCPC 3-6. We measured CBF in whole brain and regions of interest (ROIs) including frontal, parietal, and temporal cortex, caudate, putamen, thalamus, and brainstem using pulsed ASL. We compared CBF between outcome groups using Wilcoxon Rank-Sum and performed logistic regression to associate each region's CBF with outcome, accounting for age, sex, and time between arrest and MRI. RESULTS: Forty-eight patients were analyzed (median age 2.8 [IQR 0.95, 8.8] years, 65% male). Sixty-nine percent had unfavorable outcome. Time from arrest to MRI was 4 [3,5] days and similar between outcome groups (p = 0.39). Whole brain median CBF was greater for unfavorable compared to favorable groups (28.3 [20.9,33.0] vs. 19.6 [15.3,23.1] ml/100 g/min, p = 0.007), as was CBF in individual ROIs. Greater CBF in the whole brain and individual ROIs was associated with higher odds of unfavorable outcome after controlling for age, sex, and days from arrest to MRI (aOR for whole brain 19.08 [95% CI 1.94, 187.41]). CONCLUSION: CBF measured 3-5 days after pediatric cardiac arrest by ASL MRI was independently associated with unfavorable outcome.

Design and Harmonization Approach for the Multi-Institutional Neurocognitive Discovery Study (MINDS) of Adult Congenital Heart Disease (ACHD) Neuroimaging Ancillary Study: A Technical Note.

Dramatic advances in the management of congenital heart disease (CHD) have improved survival to adulthood from less than 10% in the 1960s to over 90% in the current era, such that adult CHD (ACHD) patients now outnumber their pediatric counterparts. ACHD patients demonstrate domain-specific neurocognitive deficits associated with reduced quality of life that include deficits in educational attainment and social interaction. Our hypothesis is that ACHD patients exhibit vascular brain injury and structural/physiological brain alterations that are predictive of specific neurocognitive deficits modified by behavioral and environmental enrichment proxies of cognitive reserve (e.g., level of education and lifestyle/social habits). This technical note describes an ancillary study to the National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Heart Network (PHN) "Multi-Institutional Neurocognitive Discovery Study (MINDS) in Adult Congenital Heart Disease (ACHD)". Leveraging clinical, neuropsychological, and biospecimen data from the parent study, our study will provide structural-physiological correlates of neurocognitive outcomes, representing the first multi-center neuroimaging initiative to be performed in ACHD patients. Limitations of the study include recruitment challenges inherent to an ancillary study, implantable cardiac devices, and harmonization of neuroimaging biomarkers. Results from this research will help shape the care of ACHD patients and further our understanding of the interplay between brain injury and cognitive reserve.

Single Ventricle Reconstruction III: Brain Connectome and Neurodevelopmental Outcomes: Design, Recruitment, and Technical Challenges of a Multicenter, Observational Neuroimaging Study.

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

Contributions to auditory system conduction velocity: insights with multi-modal neuroimaging and machine learning in children with ASD and XYY syndrome.

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.

Single Ventricle Reconstruction III: Brain Connectome and Neurodevelopmental Outcomes: Design, Recruitment, and Technical Challenges of a Multicenter, Observational Neuroimaging Study.

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred related to difficulties with: 1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and 2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by 1) adding additional study sites, 2) increasing the frequency of meetings with site coordinators and 3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms. Trial registration number: ClinicalTrials.gov Registration Number: NCT02692443.

Resting-State Activity in Children: Replicating and Extending Findings of Early Maturation of Alpha Rhythms in Autism Spectrum Disorder.

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.

Differential Maturation of Auditory Cortex Activity in Young Children with Autism and Typical Development.

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.

Association Between Quantitative Diffusion Weighted Magnetic Resonance Neuroimaging and Outcome After Pediatric Cardiac Arrest.

BACKGROUND AND OBJECTIVES: Diffusion magnetic resonance imaging (MRI) can quantify extent of hypoxic-ischemic brain injury after cardiac arrest. Our objective was to determine the association between adult-derived threshold of apparent diffusion coefficient (ADC) <650x10-6mm2/s in >10% of brain tissue and unfavorable outcome after pediatric cardiac arrest. Since ADC decreases exponentially as a function of increasing age, we determined association 1) having >10% of brain tissue below a novel age-dependent ADC threshold, and 2) age-normalized whole brain mean ADC and unfavorable outcome. METHODS: Retrospective study of patients ≤18 years old who had cardiac arrest and a clinically obtained brain MRI within 7 days. Primary outcome was unfavorable neurologic status at hospital discharge based on Pediatric Cerebral Performance Category (PCPC) score. ADC images were extracted from three-direction diffusion imaging. We determined whether each patient had >10% of voxels with ADC below prespecified thresholds. We computed whole brain mean ADC for each patient. RESULTS: One-hundred-thirty-four patients were analyzed. Patients with ADC <650x10-6mm2/s in >10% of voxels had 15 times higher odds (95%CI 5, 65) of unfavorable outcome compared to patients with ADC <650x10-6mm2/s (AUROC 0.72 [95%CI 0.63, 0.80]). This ADC criteria had a sensitivity and specificity of 0.49 and 0.94, and positive and negative predictive values of 0.93 and 0.52 for unfavorable outcome. The age-dependent ADC threshold that yielded optimal sensitivity and specificity for unfavorable outcome was <300x10-6mm2/s below each patient's predicted whole brain mean ADC. The sensitivity, specificity, positive and negative predictive values for this ADC threshold were 0.53, 0.96, 0.96, and 0.54, respectively (OR: 26.4 [95%CI 7.5, 168.3]; AUROC 0.74 [95%CI 0.66, 0.83]). Lower age-normalized whole brain mean ADC was also associated with unfavorable outcome (OR 0.42 [0.24, 0.64], AUROC 0.76 [95%CI 0.66, 0.82]). DISCUSSION: Quantitative diffusion thresholds on MRI within 7 days after cardiac arrest were associated with unfavorable outcome in children. Age-independent ADC threshold was highly specific for predicting unfavorable outcome. However, specificity and sensitivity increased when using age-dependent ADC thresholds. Age-dependent ADC thresholds may improve prognostic accuracy and require further investigation in larger cohorts. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that quantitative diffusion-weighted imaging (DWI) within 7 days post-arrest can predict an unfavorable clinical outcome in children.

Two mechanisms facilitate regional independence between brain regions based on an examination of alpha-band activity in healthy control adult males.

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.

Peak Alpha Frequency and Thalamic Structure in Children with Typical Development and Autism Spectrum Disorder.

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 (R2 = 0.12, p = 0.01) but not ASD (R2 = 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.

Frequency drift in MR spectroscopy at 3T.

PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 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.

Maturation of Auditory Cortex Neural Activity in Children and Implications for Auditory Clinical Markers in Diagnosis.

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.

A Multimodal Study of the Contributions of Conduction Velocity to the Auditory Evoked Neuromagnetic Response: Anomalies in Autism Spectrum Disorder.

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.

Effect of age and neurofibromatosis type 1 status on white matter integrity in the optic radiations.

BACKGROUND: Adults with neurofibromatosis type 1 (NF1) have decreased white matter integrity, but differences in children with NF1 have not been described. Defining normal values for diffusion tensor imaging (DTI) measures, especially in the optic radiations, is important to the development of DTI as a potential biomarker of visual acuity in children with optic pathway glioma. This study examines the effect of age and NF1 status on DTI measures in children. METHODS: In this retrospective study, MR imaging including DTI was conducted in 93 children (40 children with NF1 and 53 healthy controls) between 0 and 14 years of age. Regression models of age, sex, and NF1 status on DTI measures were evaluated, and tract-based spatial statistics (TBSS) compared DTI measures in age-matched NF1 to non-NF1 cohorts. RESULTS: Fractional anisotropy, radial diffusivity, and mean diffusivity in white matter tracts of the optic radiations varied with age and were best modeled by a logarithmic function. Age-related DTI measure change was different in NF1 versus non-NF1 subjects. Normal values and 95% confidence intervals for age 0.5-12 years were derived for both groups. Differences in DTI measures between NF1 and non-NF1 groups at a range of ages were shown diffusely throughout the cerebral white matter using TBSS. CONCLUSIONS: Children with NF1 demonstrate increased diffusion throughout the brain compared to children without NF1 suggesting a potentially altered developmental trajectory of optic radiation microstructure. Defining normal values for white matter integrity in children with NF1 may help target early intervention efforts in this vulnerable group.

Abnormal Auditory Mismatch Fields in Children and Adolescents With 16p11.2 Deletion and 16p11.2 Duplication.

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).

Correlation between diffusion tensor imaging parameters of the distal femoral physis and adjacent metaphysis, and subsequent adolescent growth.

BACKGROUND: Diffusion-tensor imaging (DTI) depicts the movement of water through columns of cartilage and newly formed bone and provides information about velocity of growth and growth potential. OBJECTIVE: To determine the correlation between DTI tractography parameters of the distal femoral physis and metaphysis and the height change after DTI in pubertal and post-pubertal children. MATERIALS AND METHODS: We retrospectively analyzed DTI images of the knee in 47 children with a mean age of 14.1 years in a 2-year period. In sagittal echoplanar DTI studies, regions of interest were placed in the femoral physis. Tractography was performed using a fractional anisotropy threshold of 0.15 and a maximum turning angle of 40°. The sample was divided to assess short-term and long-term growth after DTI. Short-term growth (n=25) was the height change between height at MRI and 1 year later. Long-term growth (n=36) was the height gain between height at MRI and at the growth plateau. RESULTS: For the short-term group, subjects with larger tract volume (R2=0.40) and longer track lengths (R2=0.38) had larger height gains (P<0.01). For the long-term group, subjects with larger tract volume (R2=0.43) and longer track lengths (R2=0.32) had a larger height gain at the growth plateau (P<0.01). Intra- and inter-observer variability were good-excellent. CONCLUSION: Follow-up data of growth 1 year after DTI evaluation and at skeletal maturity confirms that DTI parameters are associated with the amount of post-imaging growth.

Relationship of renal apparent diffusion coefficient and functional MR urography in children with pelvicalyceal dilation.

OBJECTIVE: The aim is to evaluate the age-related changes and relationship of renal apparent diffusion coefficient (ADC) against the morphological and functional changes detected by functional magnetic resonance urography (fMRU) in children with pelvicalyceal dilation, with suspected or known ureteropelvic junction obstruction. MATERIALS AND METHODS: We retrospectively analyzed fMRUs with diffusion-weighted imaging (DWI) of the kidney in 35 subjects (25 males; median age: 7.1 years, range: 0.3-22.7 years) with 70 kidneys (40 with pelvicalyceal dilation and 30 with no pelvicalyceal dilation). Inclusion criteria were pelvicalyceal dilation, the absence of duplex kidneys and no ureteric dilation. DWI was performed with 3 diffusion gradient directions (b values = 0, 200, 500, 800 and 1,000 s/mm2). Metrics for fMRU included calyceal and renal transit times (CTT, RTT), time-to-peak (TTP), differential renal function based on volume (vDRF), Patlak number (pDRF) and combined volume and Patlak number (vpDRF). The grades of pelvicalyceal dilation, cortical thinning and corticomedullary differentiation were evaluated. The relationship between ADC values and the fMRU parameters was analyzed. RESULTS: ADC increases with age in kidneys without pelvicalyceal dilation (R2=0.37, P<0.001). Renal ADC does not correlate with any of the morphological or fMRU parameters (P>0.07). The median ADC of kidneys without pelvicalyceal dilation was 3.73×10-3 mm2/s (range: 2.78-5.37×0-3 mm2/s) and the median ADC of kidneys with pelvicalyceal dilation was 3.82×10-3 mm2/s (range: 2.70-5.70×10-3 mm2/s). There was no correlation between ADC and the absolute differences of vDRF or pDRF (P>0.33). CONCLUSION: Renal ADC does not correlate with morphological and functional results of fMRU changes in children with pelvicalyceal dilation due to suspected or known ureteropelvic junction obstruction.

Children with Autism Spectrum Disorder Demonstrate Regionally Specific Altered Resting-State Phase-Amplitude Coupling.

Studies suggest that individuals with autism spectrum disorder (ASD) exhibit altered electrophysiological alpha to gamma phase-amplitude coupling (PAC). Preliminary reports with small samples report conflicting findings regarding the directionality of the alpha to gamma PAC alterations in ASD. The present study examined resting-state activity throughout the brain in a relatively large sample of 119 children with ASD and 47 typically developing children. Children with ASD demonstrated regionally specific abnormalities in alpha to low-gamma PAC, with increased alpha to low-gamma PAC for a central midline source and decreased PAC at lateral sources. Group differences in local gamma-band power did not account for the regional group differences in alpha to low-gamma PAC. Moreover, local alpha power did not significantly modulate alpha to low-gamma PAC estimates. Finally, PAC estimates were correlated with Social Responsiveness Scale (SRS) indicating clinical relevance of the PAC metric. In conclusion, alpha to low-gamma PAC alterations in ASD demonstrate a heterogeneous spatial profile consistent with previous studies and were related to symptom severity.