Tract- and gray matter- based spatial statistics show white matter and gray matter microstructural differences in autistic males.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition commonly studied in the context of early childhood. As ASD is a life-long condition, understanding the characteristics of brain microstructure from adolescence into adulthood and associations to clinical features is critical for improving outcomes across the lifespan. In the current work, we utilized Tract Based Spatial Statistics (TBSS) and Gray Matter Based Spatial Statistics (GBSS) to examine the white matter (WM) and gray matter (GM) microstructure in neurotypical (NT) and autistic males. Methods: Multi-shell diffusion MRI was acquired from 78 autistic and 81 NT males (12-to-46-years) and fit to the DTI and NODDI diffusion models. TBSS and GBSS were performed to analyze WM and GM microstructure, respectively. General linear models were used to investigate group and age-related group differences. Within the ASD group, relationships between WM and GM microstructure and measures of autistic symptoms were investigated. Results: All dMRI measures were significantly associated with age across WM and GM. Significant group differences were observed across WM and GM. No significant age-by-group interactions were detected. Within the ASD group, positive relationships with WM microstructure were observed with ADOS-2 Calibrated Severity Scores. Conclusion: Using TBSS and GBSS our findings provide new insights into group differences of WM and GM microstructure in autistic males from adolescence into adulthood. Detection of microstructural differences across the lifespan as well as their relationship to the level of autistic symptoms will deepen to our understanding of brain-behavior relationships of ASD and may aid in the improvement of intervention options for autistic adults.

A comparison of resting-state eyes-closed and dark-room alpha-band activity in children.

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.

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.

Gray matter microstructure differences in autistic males: A gray matter based spatial statistics study.

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition. Understanding the brain's microstructure and its relationship to clinical characteristics is important to advance our understanding of the neural supports underlying ASD. In the current work, we implemented Gray-Matter Based Spatial Statistics (GBSS) to examine and characterize cortical microstructure and assess differences between typically developing (TD) and autistic males. METHODS: A multi-shell diffusion MRI (dMRI) protocol was acquired from 83 TD and 70 autistic males (5-to-21-years) and fit to the DTI and NODDI models. GBSS was performed for voxelwise analysis of cortical gray matter (GM). General linear models were used to investigate group differences, while age-by-group interactions assessed age-related differences between groups. Within the ASD group, relationships between cortical microstructure and measures of autistic symptoms were investigated. RESULTS: All dMRI measures were significantly associated with age across the GM skeleton. Group differences and age-by-group interactions are reported. Group-wise increases in neurite density in autistic individuals were observed across frontal, temporal, and occipital regions of the right hemisphere. Significant age-by-group interactions of neurite density were observed within the middle frontal gyrus, precentral gyrus, and frontal pole. Negative relationships between neurite dispersion and the ADOS-2 Calibrated Severity Scores (CSS) were observed within the ASD group. DISCUSSION: Findings demonstrate group and age-related differences between groups in neurite density in ASD across right-hemisphere brain regions supporting cognitive processes. Results provide evidence of altered neurodevelopmental processes affecting GM microstructure in autistic males with implications for the role of cortical microstructure in the level of autistic symptoms. CONCLUSION: Using dMRI and GBSS, our findings provide new insights into group and age-related differences of the GM microstructure in autistic males. Defining where and when these cortical GM differences arise will contribute to our understanding of brain-behavior relationships of ASD and may aid in the development and monitoring of targeted and individualized interventions.

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.

Applications of advanced diffusion MRI in early brain development: a comprehensive review.

Brain development follows a protracted developmental timeline with foundational processes of neurodevelopment occurring from the third trimester of gestation into the first decade of life. Defining structural maturational patterns of early brain development is a critical step in detecting divergent developmental trajectories associated with neurodevelopmental and psychiatric disorders that arise later in life. While considerable advancements have already been made in diffusion magnetic resonance imaging (dMRI) for pediatric research over the past three decades, the field of neurodevelopment is still in its infancy with remarkable scientific and clinical potential. This comprehensive review evaluates the application, findings, and limitations of advanced dMRI methods beyond diffusion tensor imaging, including diffusion kurtosis imaging (DKI), constrained spherical deconvolution (CSD), neurite orientation dispersion and density imaging (NODDI) and composite hindered and restricted model of diffusion (CHARMED) to quantify the rapid and dynamic changes supporting the underlying microstructural architectural foundations of the brain in early life.

Automated motion artifact detection in early pediatric diffusion MRI using a convolutional neural network.

Diffusion MRI (dMRI) is a widely used method to investigate the microstructure of the brain. Quality control (QC) of dMRI data is an important processing step that is performed prior to analysis using models such as diffusion tensor imaging (DTI) or neurite orientation dispersion and density imaging (NODDI). When processing dMRI data from infants and young children, where intra-scan motion is common, the identification and removal of motion artifacts is of the utmost importance. Manual QC of dMRI data is (1) time-consuming due to the large number of diffusion directions, (2) expensive, and (3) prone to subjective errors and observer variability. Prior techniques for automated dMRI QC have mostly been limited to adults or school-age children. Here, we propose a deep learning-based motion artifact detection tool for dMRI data acquired from infants and toddlers. The proposed framework uses a simple three-dimensional convolutional neural network (3DCNN) trained and tested on an early pediatric dataset of 2,276 dMRI volumes from 121 exams acquired at 1 month and 24 months of age. An average classification accuracy of 95% was achieved following four-fold cross-validation. A second dataset with different acquisition parameters and ages ranging from 2-36 months (consisting of 2,349 dMRI volumes from 26 exams) was used to test network generalizability, achieving 98% classification accuracy. Finally, to demonstrate the importance of motion artifact volume removal in a dMRI processing pipeline, the dMRI data were fit to the DTI and NODDI models and the parameter maps were compared with and without motion artifact removal.

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.

MEG-PLAN: a clinical and technical protocol for obtaining magnetoencephalography data in minimally verbal or nonverbal children who have autism spectrum disorder.

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.

Inhibitory Control in Children 4-10 Years of Age: Evidence From Functional Near-Infrared Spectroscopy Task-Based Observations.

Executive function (EF) is essential to child development, with associated skills beginning to emerge in the first few years of life and continuing to develop into adolescence and adulthood. The prefrontal cortex (PFC), which follows a neurodevelopmental timeline similar to EF, plays an important role in the development of EF. However, limited research has examined prefrontal function in young children due to limitations of currently available neuroimaging techniques such as functional resonance magnetic imaging (fMRI). The current study developed and applied a multimodal Go/NoGo task to examine the EF component of inhibitory control in children 4-10 years of age. Cortical activity was measured using a non-invasive and child-friendly neuroimaging technique - functional near-infrared spectroscopy (fNIRS). Children's response accuracy and reaction times were captured during the fNIRS session and compared with responses obtained using the standardized assessments from NIH Toolbox cognition battery. Results showed significant correlations between the behavioral measures during the fNIRS session and the standardized EF assessments, in line with our expectations. Results from fNIRS measures demonstrated a significant, age-independent effect of inhibitory control (IC) in the right PFC (rPFC), and an age-dependent effect in the left orbitofrontal cortex (lOFC), consistent with results in previous studies using fNIRS and fMRI. Thus, the new task designed for fNIRS was suitable for examining IC in young children, and results showed that fNIRS measures can reveal prefrontal IC function.

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 MEG Study of Acute Arbaclofen (STX-209) Administration.

Several electrophysiological parameters, including the auditory evoked response component M50/M100 latencies and the phase synchrony of transient and steady-state gamma-band oscillations have been implicated as atypical (to various extents) in autism spectrum disorder (ASD). Furthermore, some hypotheses suggest that an underlying neurobiological mechanism for these observations might be atypical local circuit function indexed by atypical levels of inhibitory neurotransmitter, GABA. This study was a randomized, placebo-controlled, double-blind, escalating-dose, acute investigation conducted in 25 14-18 year-old adolescents with ASD. The study assessed the sensitivity of magnetoencephalography (MEG) and MEGAPRESS "GABA" magnetic resonance spectroscopy (MRS) to monitor dose-dependent acute effects, as well as seeking to define properties of the pre-drug "baseline" electrophysiological and GABA signatures that might predict responsiveness to the GABA-B agonist, arbaclofen (STX-209). Overall, GABA levels and gamma-band oscillatory activity showed no acute changes at either low (15 mg) or high (30 mg) dose. Evoked M50 response latency measures tended to shorten (normalize), but there was heterogeneity across the group in M50 latency response, with only a subset of participants (n = 6) showing significant M50 latency shortening, and only at the 15 mg dose. Findings thus suggest that MEG M50 latency measures show acute effects of arbaclofen administration in select individuals, perhaps reflecting effective target engagement. Whether these subjects have a greater trend towards clinical benefit remains to be established. Finally, findings also provide preliminary support for the use of objective electrophysiological measures upon which to base inclusion for optimal enrichment of populations to be included in full-scale clinical trials of arbaclofen.

Abnormal Auditory Mismatch Fields in Children and Adolescents with 47,XYY Syndrome.

47,XYY syndrome (XYY) is one of the common forms of sex chromosome aneuploidy in males. XYY males tend to have tall stature, early speech, motor delays, social and behavioral challenges, and a high rate of language impairment. Recent studies indicate that 20-40% of males with XYY meet diagnostic criteria for autism spectrum disorder (ASD; the rate in the general population is 1-2%). Although many studies have examined the neural correlates of language impairment in ASD, few similar studies have been conducted on individuals with XYY. Studies using magnetoencephalography (MEG) in idiopathic ASD (ASD-I) have demonstrated delayed neurophysiological responses to changes in the auditory stream, revealed in the mismatch negativity or its magnetic counterpart, the mismatch field (MMF). This study investigated whether similar findings are observed in XYY-associated ASD and whether delayed processing is also present in individuals with XYY without ASD. MEG measured MMFs arising from the left and the right superior temporal gyrus during an auditory oddball paradigm with vowel stimuli (/a/ and /u/) in children/adolescents with XYY both with and without a diagnosis of ASD, as well as in those with ASD-I and in typically developing controls (TD). Ninety male participants (6-17 years old) were included in the final analyses (TD, n = 38, 11.50 ± 2.88 years; ASD-I, n = 21, 13.83 ± 3.25 years; XYY without ASD, n = 15, 12.65 ± 3.91 years; XYY with ASD, n = 16, 12.62 ± 3.19 years). The groups did not differ significantly in age (p > 0.05). There was a main effect of group on MMF latency (p < 0.001). Delayed MMF latencies were found in participants with XYY both with and without an ASD diagnosis, as well as in the ASD-I group compared to the TD group (ps < 0.001). Furthermore, participants with XYY (with and without ASD) showed a longer MMF latency than the ASD-I group (ps < 0.001). There was, however, no significant difference in MMF latency between individuals with XYY with ASD and those with XYY without ASD. Delayed MMF latencies were associated with severity of language impairment. Our findings suggest that auditory MMF latency delays are pronounced in this specific Y chromosome aneuploidy disorder, both with and without an ASD diagnosis, and thus may implicate the genes of the Y chromosome in mediating atypical MMF activity.

Abnormal maturation of the resting-state peak alpha frequency in children with autism spectrum disorder.

Age-related changes in resting-state (RS) neural rhythms in typically developing children (TDC) but not children with autism spectrum disorder (ASD) suggest that RS measures may be of clinical use in ASD only for certain ages. The study examined this issue via assessing RS peak alpha frequency (PAF), a measure previous studies, have indicated as abnormal in ASD. RS magnetoencephalographic (MEG) data were obtained from 141 TDC (6.13-17.70 years) and 204 ASD (6.07-17.93 years). A source model with 15 regional sources projected the raw MEG surface data into brain source space. PAF was identified in each participant from the source showing the largest amplitude alpha activity (7-13 Hz). Given sex differences in PAF in TDC (females > males) and relatively few females in both groups, group comparisons were conducted examining only male TDC (N = 121) and ASD (N = 183). Regressions showed significant group slope differences, with an age-related increase in PAF in TDC (R2 = 0.32) but not ASD (R2 = 0.01). Analyses examining male children below or above 10-years-old (median split) indicated group effects only in the younger TDC (8.90 Hz) and ASD (9.84 Hz; Cohen's d = 1.05). In the older ASD, a higher nonverbal IQ was associated with a higher PAF. In the younger TDC, a faster speed of processing was associated with a higher PAF. PAF as a marker for ASD depends on age, with a RS alpha marker of more interest in younger versus older children with ASD. Associations between PAF and cognitive ability were also found to be age and group specific.

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.

Delayed Auditory Evoked Responses in Autism Spectrum Disorder across the Life Span.

The M50 and M100 auditory evoked responses reflect early auditory processes in the primary/secondary auditory cortex. Although previous M50 and M100 studies have been conducted on individuals with autism spectrum disorder (ASD) and indicate disruption of encoding simple sensory information, analogous investigations of the neural correlates of auditory processing through development from children into adults are very limited. Magnetoencephalography was used to record signals arising from the left and right superior temporal gyrus during auditory presentation of tones to children/adolescents and adults with ASD as well as typically developing (TD) controls. One hundred and thirty-two participants (aged 6-42 years) were included into the final analyses (children/adolescents: TD, n = 36, 9.21 ± 1.6 years; ASD, n = 58, 10.07 ± 2.38 years; adults: TD, n = 19, 26.97 ± 1.29 years; ASD, n = 19, 23.80 ± 6.26 years). There were main effects of group on M50 and M100 latency (p < 0.001) over hemisphere and frequency. Delayed M50 and M100 latencies were found in participants with ASD compared to the TD group, and earlier M50 and M100 latencies were associated with increased age. Furthermore, there was a statistically significant association between language ability and both M50 and M100 latencies. Importantly, differences in M50 and M100 latencies between TD and ASD cohorts, often reported in children, persisted into adulthood, with no evidence supporting latency convergence.