Abnormal auditory and language pathways in children with 16p11.2 deletion

Copy number variations at chromosome 16p11.2 contribute to neurodevelopmental disorders, including autism spectrum disorder (ASD). This study seeks to improve our understanding of the biological basis of behavioral phenotypes common in ASD, in particular the prominent and prevalent disruption of spoken language seen in children with the 16p11.2 BP4–BP5 deletion. We examined the auditory and language white matter pathways with diffusion MRI in a cohort of 36 pediatric deletion carriers and 45 age-matched controls. Diffusion MR tractography of the auditory radiations and the arcuate fasciculus was performed to generate tract specific measures of white matter microstructure. In both tracts, deletion carriers exhibited significantly higher diffusivity than that of controls. Cross-sectional diffusion parameters in these tracts changed with age with no group difference in the rate of maturation. Within deletion carriers, the left-hemisphere arcuate fasciculus mean and radial diffusivities were significantly negatively correlated with clinical language ability, but not non-verbal cognitive ability. Diffusion metrics in the right-hemisphere arcuate fasciculus were not predictive of language ability. These results provide insight into the link between the 16p11.2 deletion, abnormal auditory and language pathway structures, and the specific behavioral deficits that may contribute to neurodevelopmental disorders such as ASD

Neural Correlates of Auditory Processing in ASD: Towards Subpopulations and Targeted Therapy

Evidence for Central Auditory Processing Disorder (CAPD) in ASD can be identified in auditory cortex neuronal activity, recorded by magnetoencephalography (MEG). Key auditory evoked neuromagnetic response (M50 ~50ms, and M100 ~100ms) components have been found to be delayed in both children and adults with ASD. The heterogeneity of phenotypic expression in ASD is also evident in such brain signatures, leading to the suggestion that they might form the basis for stratification of subpopulations. This proposal advances the concept of stratification in ASD using a more linguistically-related probe, Lexical Oscillatory Alpha Desynchronization (LOAD), which we have shown to be associated with clinical language assessments. We examine the hypothesis that atypical central auditory processing (CAP) in a sub-population of children with ASD can manifest as over-attention to acoustic details of spoken words, compromising the ability to abstract a unitary object perception, and thus compromising downstream language ability. The first aim assesses the LOAD response in a repetition priming paradigm to define a subpopulation of children with such a CAPD manifestation. The second aim examines the hypothesis that appropriate de-emphasis or removal of such acoustic distractions using digital signal processing (DSP) will normalize the LOAD response with the ultimate, future goal of examining clinical language improvement with such DSP in the form of a hearing aid, or i-phone app

Functional and structural correlates of the aging brain: Relating visual cortex (V1) gamma band responses to age‐related structural change

The gamma band response is thought to be a key neural signature of information processing in the mammalian brain, yet little is known about how age-related maturation influences the gamma-band response. Recent MRI based studies have shown that brain maturation is accompanied by clear structural changes in both grey and white matter, yet the correspondence of these changes to brain function is unclear. The objective of this study was to relate visual cortex (V1) gamma-band responses to age-related structural change. We evaluated MEG measured gamma-band responses to contrast gratings stimuli and structural MRIs from participants observed from 2 separate research centers (MEG lab at CUBRIC, Cardiff University, UK, and the Lurie Family Foundations MEG Imaging Center, (CHOP) at the Children’s Hospital of Philadelphia). Pooled participant data (N=59) ranged in age from 8.7 to 45.3 yrs. We assessed linear associations between age and MEG gamma-band frequency and amplitude, as well as between age and MRI volumetric parameters of the occipital lobe. Our MEG findings revealed a significant negative correlation for gamma band frequency vs. age. Volumetric brain analysis from the occipital lobe also revealed significant negative correlations between age and the cortical thickness of pericalcarine and cuneus areas. Our functional MEG and structural MRI findings shows regionally specific changes due to maturation and may thus be informative for understanding physiological processes of neural development, maturation, and age-related decline. In addition, this study represents (to our knowledge), the first published demonstration of multi-centre data sharing across MEG centers

Functional and structural correlates of the aging brain: Relating visual cortex (V1) gamma band responses to age-related structural change

The gamma band response is thought to be a key neural signature of information processing in the mammalian brain, yet little is known about how age-related maturation influences the gamma-band response. Recent MRI based studies have shown that brain maturation is accompanied by clear structural changes in both grey and white matter, yet the correspondence of these changes to brain function is unclear. The objective of this study was to relate visual cortex (V1) gamma-band responses to age-related structural change. We evaluated MEG measured gamma-band responses to contrast gratings stimuli and structural MRIs from participants observed from 2 separate research centers (MEG lab at CUBRIC, Cardiff University, UK, and the Lurie Family Foundations MEG Imaging Center, (CHOP) at the Children’s Hospital of Philadelphia). Pooled participant data (N=59) ranged in age from 8.7 to 45.3 yrs. We assessed linear associations between age and MEG gamma-band frequency and amplitude, as well as between age and MRI volumetric parameters of the occipital lobe. Our MEG findings revealed a significant negative correlation for gamma band frequency vs. age. Volumetric brain analysis from the occipital lobe also revealed significant negative correlations between age and the cortical thickness of pericalcarine and cuneus areas. Our functional MEG and structural MRI findings shows regionally specific changes due to maturation and may thus be informative for understanding physiological processes of neural development, maturation, and age-related decline. In addition, this study represents (to our knowledge), the first published demonstration of multi-centre data sharing across MEG centers

Neuromagnetic responses to tactile stimulation of the fingers: Evidence for reduced cortical inhibition for children with Autism Spectrum Disorder and children with epilepsy

The purpose of this study was to compare somatosensory responses from a group of children with epilepsy and a group of children with autism spectrum disorder (ASD), with age matched TD controls. We hypothesized that the magnitude of the tactile “P50m” somatosensory response would be reduced in both patient groups, possibly due to reduced GABAergic signaling as has been implicated in a variety of previous animal models and in vivo human MRS studies. We observed significant (~25%) decreases in tactile P50m dipole moment values from the source localized tactile P50m response, both for children with epilepsy and for children with ASD. In addition, the latency of the tactile P50m peak was observed to be equivalent between TD and ASD groups but was significantly delayed in children with epilepsy by ~6ms. Our data support the hypothesis of impaired GABAergic signaling in both children with ASD and children with epilepsy. Further work is needed to replicate these findings and directly relate them to both in vivo measures of GABA via e.g. magnetic resonance spectroscopy and psychophysical assessments of somatosensory function, and behavioral indices. Keywords: Autism Spectrum Disorder, Epilepsy, Magnetoencephalography (MEG), Post-excitatory inhibition, Somatosensory evoked fields (SEFS), Tactile stimulatio

Maturation of auditory neural processes in autism spectrum disorder — A longitudinal MEG study

Background: Individuals with autism spectrum disorder (ASD) show atypical brain activity, perhaps due to delayed maturation. Previous studies examining the maturation of auditory electrophysiological activity have been limited due to their use of cross-sectional designs. The present study took a first step in examining magnetoencephalography (MEG) evidence of abnormal auditory response maturation in ASD via the use of a longitudinal design. Methods: Initially recruited for a previous study, 27 children with ASD and nine typically developing (TD) children, aged 6- to 11-years-old, were re-recruited two to five years later. At both timepoints, MEG data were obtained while participants passively listened to sinusoidal pure-tones. Bilateral primary/secondary auditory cortex time domain (100 ms evoked response latency (M100)) and spectrotemporal measures (gamma-band power and inter-trial coherence (ITC)) were examined. MEG measures were also qualitatively examined for five children who exhibited “optimal outcome”, participants who were initially on spectrum, but no longer met diagnostic criteria at follow-up. Results: M100 latencies were delayed in ASD versus TD at the initial exam (~19 ms) and at follow-up (~18 ms). At both exams, M100 latencies were associated with clinical ASD severity. In addition, gamma-band evoked power and ITC were reduced in ASD versus TD. M100 latency and gamma-band maturation rates did not differ between ASD and TD. Of note, the cohort of five children that demonstrated “optimal outcome” additionally exhibited M100 latency and gamma-band activity mean values in-between TD and ASD at both timepoints. Though justifying only qualitative interpretation, these “optimal outcome” related data are presented here to motivate future studies. Conclusions: Children with ASD showed perturbed auditory cortex neural activity, as evidenced by M100 latency delays as well as reduced transient gamma-band activity. Despite evidence for maturation of these responses in ASD, the neural abnormalities in ASD persisted across time. Of note, data from the five children whom demonstrated “optimal outcome” qualitatively suggest that such clinical improvements may be associated with auditory brain responses intermediate between TD and ASD. These “optimal outcome” related results are not statistically significant though, likely due to the low sample size of this cohort, and to be expected as a result of the relatively low proportion of “optimal outcome” in the ASD population. Thus, further investigations with larger cohorts are needed to determine if the above auditory response phenotypes have prognostic utility, predictive of clinical outcome