Maturation of auditory cortex neural responses during infancy and toddlerhood.

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.

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.

Evaluating motor cortical oscillations and age-related change in autism spectrum disorder.

Autism spectrum disorder (ASD) is primarily characterized by impairments in social communication and the appearance of repetitive behaviors with restricted interests. Increasingly, evidence also points to a general deficit of motor tone and coordination in children and adults with ASD; yet the neural basis of motor functional impairment in ASD remains poorly characterized. In this study, we used magnetoencephalography (MEG) to (1) assess potential group differences between typically developing (TD) and ASD participants in motor cortical oscillatory activity observed on a simple button-press task and (2) to do so over a sufficiently broad age-range so as to capture age-dependent changes associated with development. Event-related desynchronization was evaluated in Mu (8-13 Hz) and Beta (15-30 Hz) frequency bands (Mu-ERD, Beta-ERD). In addition, post-movement Beta rebound (PMBR), and movement-related gamma (60-90 Hz) synchrony (MRGS) were also assessed in a cohort of 123 participants (63 typically developing (TD) and 59 with ASD) ranging in age from 8 to 24.9 years. We observed significant age-dependent linear trends in Beta-ERD and MRGS power with age for both TD and ASD groups; which did not differ significantly between groups. However, for PMBR, in addition to a significant effect of age, we also observed a significant reduction in PMBR power in the ASD group (p < 0.05). Post-hoc tests showed that this omnibus group difference was driven by the older cohort of children >13.2 years (p < 0.001) and this group difference was not observed when assessing PMBR activity for the younger PMBR groups (ages 8-13.2 years; p = 0.48). Moreover, for the older ASD cohort, hierarchical regression showed a significant relationship between PMBR activity and clinical scores of ASD severity (Social Responsiveness Scale (SRS T scores)), after regressing out the effect of age (p < 0.05). Our results show substantial age-dependent changes in motor cortical oscillations (Beta-ERD and MRGS) occur for both TD and ASD children and diverge only for PMBR, and most significantly for older adolescents and adults with ASD. While the functional significance of PMBR and reduced PMBR signaling remains to be fully elucidated, these results underscore the importance of considering age as a factor when assessing motor cortical oscillations and group differences in children with ASD.

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.

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.

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.

Auditory Evoked M100 Response Latency is Delayed in Children with 16p11.2 Deletion but not 16p11.2 Duplication.

Individuals with the 16p11.2 BP4-BP5 copy number variant (CNV) exhibit a range of behavioral phenotypes that may include mild impairment in cognition and clinical diagnoses of autism spectrum disorder (ASD). To better understand auditory processing impairments in populations with this chromosomal variation, auditory evoked responses were examined in children with the 16p11.2 deletion, 16p11.2 duplication, and age-matched controls. Stimuli consisted of sinusoidal binaural tones presented passively while children underwent recording with magnetoencephalography (MEG). The primary indicator of auditory processing impairment was the latency of the ∼100-ms "M100" auditory response detected by MEG, with the 16p11.2 deletion population exhibiting profoundly delayed M100 latencies relative to controls. This delay remained even after controlling for potential confounds such as age and cognitive ability. No significant difference in M100 latency was observed between 16p11.2 duplication carriers and controls. Additionally, children meeting diagnostic criteria for ASD (16p11.2 deletion carriers) exhibited nonsignificant latency delays when compared with the corresponding CNV carriers not meeting criteria for ASD. Present results indicate that 16p11.2 deletion is associated with auditory processing delays analogous to (but substantially more pronounced than) those previously reported in "idiopathic" ASD.

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.

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.

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.

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.

Decreased levels of γ-aminobutyric acid in temporal lobe of children with 47,XYY syndrome.

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.

Magnetoencephalography Studies of the Envelope Following Response During Amplitude-Modulated Sweeps: Diminished Phase Synchrony in Autism Spectrum Disorder.

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.

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.

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).

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 Spectrotemporal Correlate of Language Impairment in Autism Spectrum Disorder.

This study introduces an objective neurophysiological marker of language ability, the integral of event-related desynchronization in the 5-20 Hz band during 0.2-1 seconds post auditory stimulation with interleaved word/non-word tokens. This measure correlates with clinical assessment of language function in both ASD and neurotypical pediatric populations. The measure does not appear related to general cognitive ability nor autism symptom severity (beyond degree of language impairment). We suggest that this oscillatory brain activity indexes lexical search and thus increases with increased search in the mental lexicon. While specificity for language impairment in ASD remains to be determined, such an objective index has potential utility in low functioning individuals with ASD and young children during language acquisition.

Auditory evoked response delays in children with 47,XYY syndrome.

47,XYY syndrome (XYY) is a male sex chromosome disorder where individuals have an 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). Latencies of auditory evoked responses measured by magnetoencephalography have shown atypical prolongations in several neuropsychiatric and genetic disorders; specifically, delayed auditory responses have been observed in ASD. In this study, we investigated the associations of genotype and clinical phenotype with auditory processing. Whole cortex magnetoencephalography recorded during a passive auditory paradigm (500 Hz tones) was used to assess the auditory evoked response in three groups of male children: idiopathic ASD, typically developing, and XYY boys. Response waveforms were computed for left and right auditory cortex and latencies of the ∼50 ms (M50) and ∼100 ms (M100) components were determined. M50 latencies were significantly delayed compared with typically developing controls in children with ASD in the right hemisphere only, and in children with XYY in the left hemisphere only, irrespective of whether they met diagnostic criteria for ASD. Findings on the later M100 component trended in the same directions but did not attain significance, due to increased variance. Replicating previous findings, decreased M50 and M100 latencies with age were observed bilaterally. Overall, while XYY shares an electrophysiological phenotype (delayed evoked response latency) with idiopathic ASD, the hemispheric differences warrant further investigation.

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.