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.

Autistic characteristics in youth with anorexia nervosa before and after treatment.

OBJECTIVE: Cognitive characteristics common to autistic individuals are often seen in adults with anorexia nervosa (AN), raising the question of whether autistic people and people with AN may share an endophenotype. We need to examine autistic characteristics during the early stages of AN to accurately parse true symptom co-occurrence from behavioural alterations due to prolonged illness. METHODS: We conducted a post-hoc analysis examining autistic characteristics in 59 youth with AN. Adolescents and parents participating in a randomised-clinical trial for AN completed questionnaires probing autistic characteristics at baseline and treatment end. We categorised participants as above or below cut-offs of clinical indicators of autism using the Autism Probability Index (API) and the Autism Spectrum Quotient-10. RESULTS: Rates of high autistic characteristics ranged between 0% and 36% depending on the instrument used and how the data was obtained (i.e., by informant report or self-report). Paternal report of autistic characteristics differed across treatment completers versus non completers and maternal report indicated lower weight gain for those with elevated characteristics. CONCLUSIONS: Low rates of autism and fluctuations in autistic features during treatment underscore the importance of longitudinal examinations of autistic characteristics in adolescents with AN. Future studies need to replicate findings in a larger adolescent sample. TRIAL REGISTRATION: ClinicalTrails.gov Identifier NCT03928028.

Magnetoencephalography and the infant brain.

Magnetoencephalography (MEG) is a non-invasive neuroimaging technique that provides whole-head measures of neural activity with millisecond temporal resolution. Over the last three decades, MEG has been used for assessing brain activity, most commonly in adults. MEG has been used less often to examine neural function during early development, in large part due to the fact that infant whole-head MEG systems have only recently been developed. In this review, an overview of infant MEG studies is provided, focusing on the period from birth to three years. The advantages of MEG for measuring neural activity in infants are highlighted (See Box 1), including the ability to assess activity in brain (source) space rather than sensor space, thus allowing direct assessment of neural generator activity. Recent advances in MEG hardware and source analysis are also discussed. As the review indicates, efforts in this area demonstrate that MEG is a promising technology for studying the infant brain. As a noninvasive technology, with emerging hardware providing the necessary sensitivity, an expected deliverable is the capability for longitudinal infant MEG studies evaluating the developmental trajectory (maturation) of neural activity. It is expected that departures from neuro-typical trajectories will offer early detection and prognosis insights in infants and toddlers at-risk for neurodevelopmental disorders, thus paving the way for early targeted interventions.

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.

Initial Clinical Guidelines for Co-Occurring Autism Spectrum Disorder and Gender Dysphoria or Incongruence in Adolescents.

Evidence indicates an overrepresentation of youth with co-occurring autism spectrum disorders (ASD) and gender dysphoria (GD). The clinical assessment and treatment of adolescents with this co-occurrence is often complex, related to the developmental aspects of ASD. There are no guidelines for clinical care when ASD and GD co-occur; however, there are clinicians and researchers experienced in this co-occurrence. This study develops initial clinical consensus guidelines for the assessment and care of adolescents with co-occurring ASD and GD, from the best clinical practices of current experts in the field. Expert participants were identified through a comprehensive international search process and invited to participate in a two-stage Delphi procedure to form clinical consensus statements. The Delphi Method is a well-studied research methodology for obtaining consensus among experts to define appropriate clinical care. Of 30 potential experts identified, 22 met criteria as expert in co-occurring ASD and GD youth and participated. Textual data divided into the following data nodes: guidelines for assessment; guidelines for treatment; six primary clinical/psychosocial challenges: social functioning, medical treatments and medical safety, risk of victimization/safety, school, and transition to adulthood issues (i.e., employment and romantic relationships). With a cutoff of 75% consensus for inclusion, identified experts produced a set of initial guidelines for clinical care. Primary themes include the importance of assessment for GD in ASD, and vice versa, as well as an extended diagnostic period, often with overlap/blurring of treatment and assessment.

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.

A community cross-sectional survey of medical problems in 440 children with Down syndrome in New York State.

OBJECTIVE: To determine the frequency of medical problems in a large population of children with Down syndrome. STUDY DESIGN: Study population included 440 children with Down syndrome (ages 3-14 years) identified primarily through the New York Congenital Malformations Registry. Parents completed questionnaires on medical problems. RESULTS: Our study population was predominately White (92.3%), non-Hispanic (72.3%) with at least 1 college educated parent (72.3%). The prevalence of medical problems was as follows: heart disease (55%), hearing problem (39%), vision problem (39%), thyroid disease (27%), celiac disease (5%), alopecia (5%), seizures (7%), asthma/reactive airway disease (32%), diabetes (1%), and juvenile rheumatoid arthritis (0.2%). Of the children with heart disease, 58% needed surgery at a mean age of 9 months. Of the children with hearing loss, 29% were identified on newborn screening and 13% used an amplification device. Of the children with thyroid disease, 31% were diagnosed in the newborn period. Only 7% of these children with Down syndrome had no medical problem listed. CONCLUSION: Prevalence data of medical illnesses in a large population of children with Down syndrome provide us with data to support implementation of the American Academy of Pediatrics guidelines for health supervision for children with Down syndrome. The long-term health implications of the conditions we surveyed will be important for decreasing morbidity and increasing overall health and wellness into adulthood.

Spatiotemporal cerebral blood flow dynamics underlies emergence of the limbic-sensorimotor-association cortical gradient in human infancy.

Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we found the emergence of the cortical hierarchy revealed by highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increased in a biphasic pattern with initial rapid and sequentially slower rate, with break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices were associated with enhanced language and motor skills, and frontoparietal association cortices for cognitive skills. The study discovered emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy, and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning.

Functional and structural maturation of auditory cortex from 2 months to 2 years old.

In school-age children, the myelination of the auditory radiation thalamocortical pathway is associated with the latency of auditory evoked responses, with the myelination of thalamocortical axons facilitating the rapid propagation of acoustic information. Little is known regarding this auditory system function-structure association in infants and toddlers. The present study tested the hypothesis that maturation of auditory radiation white-matter microstructure (e.g., fractional anisotropy (FA); measured using diffusion-weighted MRI) is associated with the latency of the infant auditory response (P2m measured using magnetoencephalography, MEG) in a cross-sectional (2 to 24 months) as well as longitudinal cohort (2 to 29 months) of typically developing infants and toddlers. In the cross-sectional sample, non-linear maturation of P2m latency and auditory radiation diffusion measures were observed. After removing the variance associated with age in both P2m latency and auditory radiation diffusion measures, auditory radiation still accounted for significant variance in P2m latency. In the longitudinal sample, latency and FA associations could be observed at the level of a single child. Findings provide strong support for a contribution of auditory radiation white matter to rapid cortical auditory encoding processes in infants.

The maturation of infant and toddler visual cortex neural activity and associations with fine motor performance.

Our understanding of how visual cortex neural processes mature during infancy and toddlerhood is limited. Using magnetoencephalography (MEG), the present study investigated the development of visual evoked responses (VERs) in both cross-sectional and longitudinal samples of infants and toddlers 2 months to 3 years. Brain space analyses focused on N1m and P1m latency, as well as the N1m-to-P1m amplitude. Associations between VER measures and developmental quotient (DQ) scores in the cognitive/visual and fine motor domains were also examined. Results showed a nonlinear decrease in N1m and P1m latency as a function of age, characterized by rapid changes followed by slower progression, with the N1m latency plateauing at 6-7 months and the P1m latency plateauing at 8-9 months. The N1m-to-P1m amplitude also exhibited a non-linear decrease, with strong responses observed in younger infants (∼2-3 months) and then a gradual decline. Associations between N1m and P1m latency and fine motor DQ scores were observed, suggesting that infants with faster visual processing may be better equipped to perform fine motor tasks. The present findings advance our understanding of the maturation of the infant visual system and highlight the relationship between the maturation of visual system and fine motor skills. Highlights: The infant N1m and P1m latency shows a nonlinear decrease.N1m latency decreases precede P1m latency decreases.N1m-to-P1m amplitude shows a nonlinear decrease, with stronger responses in younger than older infants.N1m and P1m latency are associated with fine motor DQ.

Screening for Caregiver-Reported Feeding Concerns in Children with Autism Spectrum Disorder in a Tertiary-Care Clinic.

OBJECTIVE: Feeding concerns, primarily food selectivity, are commonly observed in children with autism spectrum disorder (ASD). Prevalence rates suggest that at least half of autistic youth have feeding difficulties. METHODS: A retrospective chart review examining records of a large cohort of autistic children (N = 746) referred for ASD evaluation was conducted. Families completed a survey regarding feeding concerns in their children before a diagnostic evaluation. RESULTS: Post hoc analyses based on retrospective chart review revealed approximately 30% of caregivers reported significant difficulty feeding their child. Young age, food selectivity, and concerns about weight were associated with increased likelihood of reported feeding difficulties. There was clear overlap between overall feeding difficulties and specific food selectivity; however, 1 in 5 children whose caregivers did not report feeding difficulties endorsed food selectivity. CONCLUSION: Findings highlight the need for multipronged approaches to screening to facilitate service prioritization by pediatric providers.

Effects of a mobile health nutrition intervention on dietary intake in children who have autism spectrum disorder.

Background: Children who have Autism Spectrum Disorder (ASD) show preferences for processed foods, such as salty and sugary snacks (SSS) and sugar-sweetened beverages (SSB), while healthier foods, such as fruits and vegetables (FV), are consumed less. Innovative tools are needed that can efficiently disseminate evidence-based interventions and engage autistic children to improve their diet. Aim: The aim of this 3-month randomized trial was to test the initial efficacy of a mobile health (mHealth) nutrition intervention on changing consumption of targeted healthy (FV) and less healthy foods/beverages (SSS, SSB) in children who have ASD, ages 6-10, who were picky eaters. Methods: Thirty-eight parent-child dyads were randomly assigned to either an intervention (technology) group or a wait list control (education) group. The intervention included behavioral skills training, a high level of personalization for dietary goals, and involved parents as "agents of change." Parents in the education group received general nutrition education and the dietary goals but did not receive skills training. Children's intake was assessed at baseline and at 3 months using 24-hour dietary recalls. Results: While there were no significant group-by-time interactions (P > 0.25) for any of the primary outcomes, we found a significant main effect of time for FV intake (P = 0.04) indicating that both groups consumed more FV at 3 months (2.58 ± 0.30 servings/day) than at baseline (2.17 ± 0.28 servings/day; P = 0.03). Children in the intervention group who consumed few FV at baseline and showed high engagement with the technology increased their FV intake by 1.5 servings/day (P < 0.01). Children's taste/smell sensitivity significantly predicted their FV intake (P = 0.0446); for each unit of lower taste/smell sensitivity (indicating greater sensory processing abnormalities), FV intake increased by 0.13 ± 0.1 servings/day. Discussion: This mHealth intervention did not yield significant between-group differences for changing consumption of targeted foods/beverages. Only children who consumed few FV at baseline and highly engaged with the technology increased their FV intake at 3 months. Future research should test additional strategies to expand the intervention's impact on a wider range of foods while also reaching a broader group of children who have ASD. This trial was registered at clinicaltrials.gov as NCT03424811.Clinical Trial Registration: This study was registered at clinicaltrials.gov as NCT03424811.

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.

Maturational trajectory of fusiform gyrus neural activity when viewing faces: From 4 months to 4 years old.

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

Biomarkers for autism spectrum disorder: opportunities for magnetoencephalography (MEG).

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