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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Maturation of hemispheric specialization for face encoding during infancy and toddlerhood.

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

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.

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.

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).

Caregiver Report of Executive Functioning in Adolescent Females With Anorexia Nervosa or Autism Spectrum Disorder.

Current literature suggesting a shared endophenotype between individuals with anorexia nervosa (AN) and autism spectrum disorder (ASD) related to executive functioning (EF) has several limitations: performance-based instead of ecologically valid measures of set-shifting are used, lack of comparisons between same-sex groups, and reliance on adult samples only. This was the first study directly comparing female youth with ASD to female youth with AN using an ecologically valid measure of EF. A secondary data analysis combined caregiver-reported EF on the Behavior Rating Inventory of Executive Functioning (BRIEF) for 22 female adolescent youth with AN and 29 female adolescent youth with ASD. EF in each group was compared to population norms, and EF was compared between groups. Compared to population norms, adolescents with AN had elevated scores on shift, initiate, and emotional control scales, and adolescents with ASD had elevated scores on all scales of the BRIEF and were more likely to have scores in the clinical range. There were significant differences between groups on all but three scales. The cognitive profiles and clinical scores of AN females were not comparable to those of ASD females. The findings reveal a clear clinical impairment in females with ASD but not in females with AN. The results do not support the hypothesis of similar real-world EF profiles between these groups. The results encourage further exploration into the similarities and distinctions between these two disorders.

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.