Brain Mechanisms for Language Processing in Adolescents With Autism Spectrum Disorder

About 30% of children with Autism Spectrum Disorder (ASD) fail to acquire spoken language.
This group of children has been seriously neglected in research conducted over the past 2
decades. Little is known about them, in part because the field lacks the tools to assess
them, and they often pose significant behavioral challenges that preclude their participation
in research studies. Among the ~70% individuals with ASD who have spoken language skills,
about 50% are language impaired; the remaining group have normal language scores on
standardized tests. Thus, there is enormous heterogeneity in verbal abilities in ASD. To
date, studies of the brain and cognitive mechanisms that underlie this heterogeneity remain
quite limited.

At the cognitive level, current research suggests that language impairment in verbal children
with ASD involves deficits in phonological working memory, as evident on tests of nonsense
word repetition. The areas of language that are most affected in this group include complex
syntax and morphology related to marking tense (Tager-Flusberg et al., 2005). There is also
considerable evidence from MRI (magnetic resonance imaging) studies of both children and
adults that there are differences in volume and asymmetry in language regions of the cortex,
specifically Broca's and Wernicke's areas. Recent studies suggest that these differences do
not necessarily track with degree of language impairment, though there are conflicting
findings in the literature. Importantly, most of the participants in cognitive and
neuroimaging studies of ASD have been adults and individuals who have relatively intact
language. Far less is known about the processes (either cognitive or neural) that might be
implicated in the minimally verbal group. This project is designed to address this issue
using two different brain imaging methods and approaches.

1. fMRI and DTI: Converging lines of evidence support the view that ASDs are disorders of
connectivity, in which abnormalities in white matter integrity and reduced coordination
of activity across brain regions give rise to core features. Recent results from our
group (Guenther; Manoach) have identified white matter anomalies in the speech network
of high-functioning verbal adults with ASD, specifically in the pathway between the left
supplementary motor area (SMA) and left ventral premotor cortex (vPMC), a pathway
involved in the initiation of speech output according to the Directions into Velocities
of Articulators (DIVA) model of speech production, a leading model of the neural
computations underlying speech. These connectivity abnormalities are revealed in both
DTI and functional connectivity analyses collected using fMRI. NOTE: IRB approval for
the collection of fMRI/DTI data will be obtained from MGH, where this portion of the
study will be carried out. Data analyses will be carried out at MGH and BU.

2. Electrophysiology: EEG/ERP It has long been known that some children with ASD fail to
respond when spoken to, cover their ears in the presence of certain sounds, yet show
highly acute hearing in other contexts. Little is known about the mechanisms that might
underlie these unusual auditory processing profiles. Abnormal neural oscillations have
been found to be an endophenotype for ASD in infants and adults. However, the picture of
how oscillations differ from those of non-clinical subjects is unclear and depends on
the age at testing. Characterizing the oscillations present in the brains of a range of
adolescents will allow us to quantify the relationship between neural activity and
severity of language impairment. The main hypothesis that will be tested in this project
is that abnormal neural connectivity in minimally verbal children with ASD profoundly
impedes the ability to perceptually organize auditory scenes into meaningful units or
objects, which has a direct effect on language development in these individuals.
Event-related brain potentials (ERPs) and frequency-based analysis of the
electroencephalogram (EEG) will be collected during passive listening tasks, to evaluate
auditory perception and the perceptual organization of tones and speech using the
mismatch negativity (MMN) paradigm (the MMN reflects passive deviance detection
processes indexing low-level acoustic processes in automatic sensory memory mechanisms,
and it has been widely investigated in studies of auditory perceptual discrimination of
tones and speech).

The investigators plan to collect these data from 3 groups of adolescents with ASD varying in
language skills (minimally verbal, verbal-language impaired, verbal-language normal) and age
and gender matched non-ASD typical adolescents. The participants will be diagnosed and tested
using a range of standardized and non-standardized assessments including IQ/cognitive level;
social abilities; ASD severity; communication skills (nonverbal). These assessments will be
carried out by trained examiners in the clinical core housed at BU.

Because many of the participants present with highly challenging behaviors and are difficult
to test, a number of innovative approaches will be taken to maximize participants' success in
completing the behavioral assessments, and then to tolerate and provide artifact-free data in
the electrophysiological and MRI portions of the study.

Overall, the investigators hypothesize that the groups tested will differ in their neural
indices of auditory perception, neural indices of perceptual organization, and induced neural
oscillations. Further, the investigators hypothesize that differences in the degree of
language impairment across these groups will be correlated with differences in the degree of
abnormality of the measured neural indices, but not in the form of the abnormality,
suggesting that the root causes of the differences across the tested subject groups are
quantitative rather than qualitative.

Inclusion Criteria:

- Between the ages of 14 and 21

- Minimally verbal (which is defined as having fewer than 10 words/phrases used
communicatively during the Autism Diagnostic Observation Schedule (ADOS) assessment

- Demonstrated minimal progress in speech acquisition despite having participated in
speech therapy for at least 18 months

- Diagnosis of Autism Spectrum Disorder (ASD)

- Verbal but language impaired (defined as more than 1.25 standard deviation below the
mean on the clinical evaluation of language fundamentals - Fourth edition (CELF-4))

- Has normal language scores (on the CELF-4)

- Is typically developing with no history of psychiatric or neurological disorders

Exclusion Criteria:

- Has contraindications to having a magnetic resonance imaging (MRI) scan (e.g.
electronic/ferromagnetic implant, clips, stents, existing or planned major dental
work)

- Has a history of significant neurological diseases

- Has a history of sensory impairment (e.g., hearing impairment)

- Has a history of disorders other than ASD

- Is currently taking antipsychotic medications.