Lisa Blaskey

MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism

Motivated by auditory and speech deficits in autism spectrum disorders (ASD), the frequency dependence of superior temporal gyrus (STG) 50 msec (M50) and 100 msec (M100) neuromagnetic auditory evoked field responses in children with ASD and typically developing controls were evaluated. Whole‐cortex magnetoencephalography (MEG) was obtained from 17 typically developing children and 25 children with ASD. Subjects were presented tones with frequencies of 200, 300, 500, and 1,000 Hz, and left and right STG M50 and M100 STG activity was examined. No M50 latency or amplitude Group differences were observed. In the right hemisphere, a Group×Frequency ANOVA on M100 latency produced a main effect for Group (P=0.01), with an average M100 latency delay of 11 msec in children with ASD. In addition, only in the control group was the expected association of earlier M100 latencies in older than younger children observed. Group latency differences remained significant when hierarchical regression analyses partialed out M100 variance associated with age, IQ, and language ability (all P‐values <0.05). Examining the right‐hemisphere 500 Hz condition (where the largest latency differences were observed), a sensitivity of 75%, a specificity of 81%, and a positive predictive value (PPV) of 86% was obtained at a threshold of 116 msec. The M100 latency delay indicates disruption of encoding simple sensory information. Given similar findings in language impaired and nonlanguage impaired ASD subjects, a right‐hemisphere M100 latency delay appears to be an electrophysiological endophenotype for autism.

GABA estimation in the Brains of Children on the Autism Spectrum: Measurement precision and regional cortical variation

(1)H magnetic resonance spectroscopy ((1)H MRS) and spectral editing methods, such as MEGA-PRESS, allow researchers to investigate metabolite and neurotransmitter concentrations in-vivo. Here we address the utilization of (1)H MRS for the investigation of GABA concentrations in the ASD brain, in three locations; motor, visual and auditory areas. An initial repeatability study (5 subjects, 5 repeated measures separated by ~5days on average) indicated no significant effect of reference metabolite choice on GABA quantitation (p>0.6). Coefficients of variation for GABA+/NAA, GABA+/Cr and GABA+/Glx were all of the order of 9-11%. Based on these findings, we investigated creatine-normalized GABA+ ratios (GABA+/Cr) in a group of (N=17) children with autism spectrum disorder (ASD) and (N=17) typically developing children (TD) for Motor, Auditory and Visual regions of interest (ROIs). Linear regression analysis of gray matter (GM) volume changes (known to occur with development) revealed a significant decrease of GM volume with Age for Motor (F(1,30)=17.92; p<0.001) and Visual F(1,16)=14.41; p<0.005 but not the Auditory ROI (p=0.55). Inspection of GABA+/Cr changes with Age revealed a marginally significant change for the Motor ROI only (F(1,30)=4.11; p=0.054). Subsequent analyses were thus conducted for each ROI separately using Age and GM volume as covariates. No group differences in GABA+/Cr were observed for the Visual ROI between TD vs. ASD children. However, the Motor and Auditory ROI showed significantly reduced GABA+/Cr in ASD (Motor p<0.05; Auditory p<0.01). The mean deficiency in GABA+/Cr from the Motor ROI was approximately 11% and Auditory ROI was approximately 22%. Our novel findings support the model of regional differences in GABA+/Cr in the ASD brain, primarily in Auditory and to a lesser extent Motor but not Visual areas.

Auditory Magnetic Mismatch Field Latency: A Biomarker for Language Impairment in Autism

BACKGROUND Auditory processing abnormalities are frequently observed in autism spectrum disorders (ASD), and these abnormalities may have sequelae in terms of clinical language impairment (LI). The present study assessed associations between language impairment and the amplitude and latency of the superior temporal gyrus magnetic mismatch field (MMF) in response to changes in an auditory stream of tones or vowels. METHODS Fifty-one children with ASD, and 27 neurotypical control subjects, all aged 6 to 15 years, underwent neuropsychological evaluation, including tests of language function, as well as magnetoencephalographic recording during presentation of tones and vowels. The MMF was identified in the difference waveform obtained from subtraction of responses to standard from deviant stimuli. RESULTS Magnetic mismatch field latency was significantly prolonged (p < .001) in children with ASD, compared with neurotypical control subjects. Furthermore, this delay was most pronounced (∼50 msec) in children with concomitant LI, with significant differences in latency between children with ASD with LI and those without (p < .01). Receiver operator characteristic analysis indicated a sensitivity of 82.4% and specificity of 71.2% for diagnosing LI based on MMF latency. CONCLUSIONS Neural correlates of auditory change detection (the MMF) are significantly delayed in children with ASD, and especially those with concomitant LI, suggesting a neurobiological basis as well as a clinical biomarker for LI in ASD.

Elevated Mean Diffusivity in the Left Hemisphere Superior Longitudinal Fasciculus in Autism Spectrum Disorders Increases with More Profound Language Impairment

The cause of autism continues to be uncertain and conventional imaging is not helpful. These investigators used DTI to study the language-related white matter tracts in a subset of patients with autism and language impairments. Eighteen patients were compared with 25 controls and showed abnormal DTI parameters in the superior longitudinal fasciculus, particularly in its temporal portion and on the left side. Thus, the white matter subserving language in these patients was abnormal. BACKGROUND AND PURPOSE: Language impairments are observed in a subset of individuals with ASD. To examine microstructural brain white matter features associated with language ability in ASD, we measured the DTI parameters of language-related white matter tracts (SLF) as well as non-language-related white matter tracts (CST) in children with ASD/+LI and ASD/−LI) and in TD. MATERIALS AND METHODS: Eighteen children with ASD/−LI (age range, 6.7–17.5 years), 17 with ASD/+LI (age range, 6.8–14.8 years), and 25 TD (age range, 6.5–18 years) were evaluated with DTI and tractography. Primary DTI parameters considered for analysis were MD and FA. RESULTS: There was a main effect of diagnostic group on age-corrected MD (P < .05) with ASD/+LI significantly elevated compared with TD. This was most pronounced for left hemisphere SLF fiber tracts and for the temporal portion of the SLF. There was significant negative correlation between left hemisphere SLF MD values and the clinical assessment of language ability. There was no main effect of diagnostic group or diagnostic group X hemisphere interaction for FA. Although there was a main effect of diagnostic group on values of MD in the CST, this did not survive hemispheric subanalysis. CONCLUSIONS: Abnormal DTI parameters (specifically significantly elevated MD values in ASD) of the SLF appear to be associated with language impairment in ASD. These elevations are particularly pronounced in the left cerebral hemisphere, in the temporal portion of the SLF, and in children with clinical language impairment.

Joint analysis of band-specific functional connectivity and signal complexity in autism.

Examination of resting state brain activity using electrophysiological measures like complexity as well as functional connectivity is of growing interest in the study of autism spectrum disorders (ASD). The present paper jointly examined complexity and connectivity to obtain a more detailed characterization of resting state brain activity in ASD. Multi-scale entropy was computed to quantify the signal complexity, and synchronization likelihood was used to evaluate functional connectivity (FC), with node strength values providing a sensor-level measure of connectivity to facilitate comparisons with complexity. Sensor level analysis of complexity and connectivity was performed at different frequency bands computed from resting state MEG from 26 children with ASD and 22 typically developing controls (TD). Analyses revealed band-specific group differences in each measure that agreed with other functional studies in fMRI and EEG: higher complexity in TD than ASD, in frontal regions in the delta band and occipital-parietal regions in the alpha band, and lower complexity in TD than in ASD in delta (parietal regions), theta (central and temporal regions) and gamma (frontal-central boundary regions); increased short-range connectivity in ASD in the frontal lobe in the delta band and long-range connectivity in the temporal, parietal and occipital lobes in the alpha band. Finally, and perhaps most strikingly, group differences between ASD and TD in complexity and FC appear spatially complementary, such that where FC was elevated in ASD, complexity was reduced (and vice versa). The correlation of regional average complexity and connectivity node strength with symptom severity scores of ASD subjects supported the overall complementarity (with opposing sign) of connectivity and complexity measures, pointing to either diminished connectivity leading to elevated entropy due to poor inhibitory regulation or chaotic signals prohibiting effective measure of connectivity.

Using Standardized Diagnostic Instruments to Classify Children with Autism in the Study to Explore Early Development

The Study to Explore Early Development (SEED) is a multi-site case–control study designed to explore the relationship between autism spectrum disorder (ASD) phenotypes and etiologies. The goals of this paper are to (1) describe the SEED algorithm that uses the Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) to classify children with ASD, (2) examine psychometric properties of different ASD classification methods, including the SEED method that incorporates rules for resolving ADI-R and ADOS discordance, and (3) determine whether restricted interests and repetitive behaviors were noted for children who had instrument discordance resolved using ADI-R social and communication scores. Results support the utility of SEED criteria when well-defined groups of children are an important clinical or research outcome.

Developmental correlation of diffusion anisotropy with auditory-evoked response

White matter diffusion anisotropy in the acoustic radiations of the auditory pathway was characterized as a function of development in children and adolescents. Auditory-evoked neuromagnetic fields were also recorded from the same individuals, and the latency of the left and right superior temporal gyrus auditory response of approximately 100 ms was also obtained. White matter diffusion anisotropy increased with age. There was a commensurate shortening of the auditory-evoked response latency with increased age as well as with increased white matter diffusion anisotropy. The significant negative correlation between structural integrity of white matter pathways and electrophysiological function (response timing) of distal cortex supports a biophysical model of developmental changes in white matter myelination, conduction velocity, and cortical response timing.

High angular resolution diffusion imaging probabilistic tractography of the auditory radiation.

BACKGROUND AND PURPOSE: The auditory radiation crosses other white matter tracts and cannot reliably be delineated or quantitatively assessed with DTI fiber tracking. This study investigates whether HARDI fiber tracking can be used to robustly delineate the full extent of the tract. MATERIALS AND METHODS: HARDI (64-direction, b=3000 s/mm2) and DTI (30-direction, b=1000 s/mm2) were acquired from 25 control participants between 8 and 26 years old. Probabilistic HARDI and DTI fiber tracking of the auditory radiation was performed with starting and filter regions automatically generated from the FreeSurfer white matter parcellation. DTI fiber tracking was performed with both the 64-direction and the 30-direction datasets. Fiber-tracking trials demonstrating connectivity from the Heschl gyrus to the medial geniculate nucleus were considered successful. RESULTS: The HARDI fiber tracking success rate was 98% and was significantly higher than the 64-direction DTI rate of 50% or the 30-direction DTI rate of 42% (P < .001). The success rates of HARDI fiber tracking for the left and right auditory radiations were not significantly different. In contrast, the left auditory radiation was successfully delineated with DTI fiber tracking at a higher rate than the right auditory radiation. CONCLUSIONS: HARDI can discriminate the complex white matter pathways at the junction of the auditory radiation and the ILF. HARDI fiber tracking can reliably delineate the auditory radiation.

Missing and Delayed Auditory Responses in Young and Older Children with Autism Spectrum Disorders

Background: The development of left and right superior temporal gyrus (STG) 50 ms (M50) and 100 ms (M100) auditory responses in typically developing (TD) children and in children with autism spectrum disorder (ASD) was examined. Reflecting differential development of primary/secondary auditory areas and supporting previous studies, it was hypothesized that whereas left and right M50 STG responses would be observed equally often in younger and older children, left and right M100 STG responses would more often be absent in younger than older children. In ASD, delayed neurodevelopment would be indicated via the observation of a greater proportion of ASD than TD subjects showing missing M100 but not M50 responses in both age groups. Missing M100 responses would be observed primarily in children with ASD with language impairment (ASD + LI) (and perhaps concomitantly lower general cognitive abilities). Methods: Thirty-five TD controls, 63 ASD without language impairment (ASD − LI), and 38 ASD + LI were recruited. Binaural tones were presented. The presence or absence of a STG M50 and M100 was scored. Subjects were grouped into younger (6–10 years old) and older groups (11–15 years old). Results: Although M50 responses were observed equally often in older and younger subjects and equally often in TD and ASD, left and right M50 responses were delayed in ASD − LI and ASD + LI. Group comparisons showed that in younger subjects M100 responses were observed more often in TD than ASD + LI (90 versus 66%, p = 0.04), with no differences between TD and ASD − LI (90 versus 76%, p = 0.14) or between ASD − LI and ASD + LI (76 versus 66%, p = 0.53). In older subjects, whereas no differences were observed between TD and ASD + LI, responses were observed more often in ASD − LI than ASD + LI. Findings were similar when splitting the ASD group into lower- and higher-cognitive functioning groups. Conclusion: Although present in all groups, M50 responses were delayed in ASD. Examining the TD data, findings indicated that by 11 years, a right M100 should be observed in 100% of subjects and a left M100 in 80% of subjects. Thus, by 11 years, lack of a left and especially right M100 offers neurobiological insight into sensory processing that may underlie language or cognitive impairment.

Artemis 123: development of a whole-head infant and young child MEG system

Background: A major motivation in designing the new infant and child magnetoencephalography (MEG) system described in this manuscript is the premise that electrophysiological signatures (resting activity and evoked responses) may serve as biomarkers of neurodevelopmental disorders, with neuronal abnormalities in conditions such as autism spectrum disorder (ASD) potentially detectable early in development. Whole-head MEG systems are generally optimized/sized for adults. Since magnetic field produced by neuronal currents decreases as a function of distance2 and infants and young children have smaller head sizes (and thus increased brain-to-sensor distance), whole-head adult MEG systems do not provide optimal signal-to-noise in younger individuals. This spurred development of a whole-head infant and young child MEG system – Artemis 123. Methods:In addition to describing the design of the Artemis 123, the focus of this manuscript is the use of Artemis 123 to obtain auditory evoked neuromagnetic recordings and resting-state data in young children. Data were collected from a 14-month-old female, an 18-month-old female, and a 48-month-old male. Phantom data are also provided to show localization accuracy. Results:Examination of Artemis 123 auditory data showed generalizability and reproducibility, with auditory responses observed in all participants. The auditory MEG measures were also found to be manipulable, exhibiting sensitivity to tone frequency. Furthermore, there appeared to be a predictable sensitivity of evoked components to development, with latencies decreasing with age. Examination of resting-state data showed characteristic oscillatory activity. Finally, phantom data showed that dipole sources could be localized with an error less than 0.5 cm. Conclusions:Artemis 123 allows efficient recording of high-quality whole-head MEG in infants four years and younger. Future work will involve examining the feasibility of obtaining somatosensory and visual recordings in similar-age children as well as obtaining recordings from younger infants. Thus, the Artemis 123 offers the promise of detecting earlier diagnostic signatures in such neurodevelopmental disorders.