Tracking Early Emergence of Sound Perception Impairments in FXS With Multimodal fNIRS/EEG

Study Overview
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Brief Summary
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Individuals with Fragile X Syndrome show differences in how they understand and learn language from infancy. They frequently have lifelong delays in speech and language as well. In addition, they experience other auditory symptoms, including being very sensitive to certain sounds as well as being more sensitive than others to loud sounds. The underlying brain activity for sound perception and speech learning in Fragile X is not well understood, especially in the infant and toddler years. This study uses behavioral assessment of speech and language abilities, neuroimaging, and hearing tests to understand how speech and hearing are different in children with Fragile X Syndrome.

Detailed Description
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Fragile X Syndrome (FXS) is the leading monogenic cause of intellectual disability and autism and is associated with extremely high risk for early delays in speech and language. While the infant years are essential to speech and language development, neural mechanisms for language impairments have been studied entirely in older children and adults with FXS. Therefore, markers for speech and language impairments are unavailable in infants and young children with FXS to predict severity, test potential mechanisms, and track response to intervention. The investigators have identified a hallmark brain-based phenotype of hyperresponsiveness to sounds in adolescents and adults with FXS. This fundamental alteration in cortical responses to sound could influence early language delays, but this phenotype has not been explored in infants or toddlers with FXS. Specifically, in this study the investigators will use simultaneous EEG/fNIRS during presentation of simple speech, stories, and nonspeech sounds to quantify and localize auditory hypersensitivity and neural differentiation in 30 preschoolers with FXS. The investigators will assess specificity through comparison with 30 typically developing controls and 30 mental-age matched children with a history of premature birth and language delays. In addition, the investigators will complete a longitudinal study (3 timepoints) of 15 infants with FXS and 15 TDC controls, with the first visit completed between 6 and 12 months of age. At each visit, the investigators will measure speech and hearing alongside cortical responses to sounds. In combination with quantitative assessment of linguistic complexity in each infant's home environment, the investigators will develop a potential model linking brain-based indicators with emergence of language delays in FXS

Official Title
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Tracking Early Emergence of Sound Perception Impairments in FXS With Multimodal fNIRS/EEG

Conditions
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Fragile X Syndrome

Intervention / Treatment
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* Other: Speech discrimination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnoses of Fragile X Syndrome, Typical Development, or History of Premature Birth able to sit independently English is spoken at home Exclusion Criteria: For all participants: no seizures in the past 6 months For typical development group and Fragile X group: not born prior to 36 weeks gestation

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Speech Sounds<br>Participants listen to speech sounds while the investigators measure electrical and hemodynamic changes in the brain. | Other: Speech discrimination<br>* Two different speech sounds are played at the same sound intensity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mullen Scales of Early Learning | change in Mullen Scales scores (age-corrected) from baseline on all subscales, including Expressive Language, Receptive Language, FIne Motor, Gross Motor, and Visual Reception. T-Scores from the Mullen Scales of Early Learning (MSEL) have a mean of 50 and a standard deviation of 10. Range=20-80. Higher scores indicate more advanced developmental skills. | at 6 month, 12 month, 18 month, 24 month, 3 year, and 4 year visits | 
| Changes in oxygenated and deoxygenated hemoglobin concentration in response to sounds in language regions of the brain | Relative increase in oxygenated versus deoxygenated hemoglobin for no sounds, low intensity sounds, and medium intensity sounds. Measured via functional Near Infrared Spectroscopy with optodes placed over frontal, temporal, and parietal language regions. | at 6 month, 12 month, 18 month, 24 month, 3 year, and 4 year visits | 
| Changes in amplitude of mismatch negativity response during sound discrimination | Electroencephalography is measured over the scalp while participant listens to speech sounds with infrequent oddball stimuli. Amplitude of the P100 for all stimuli as well as amplitude of the mismatch negativity response (frequent minus infrequent response) as well as change in these metrics over development are tracked in all groups. | at 6 month, 12 month, 18 month, 24 month, 3 year, and 4 year visits | 
| Changes in LENA vocalizations and conversational turns | LENA is a voice recording system and proprietary program that records a child's home language environment and quantifies number of sounds and words each child produces as well as complexity of home language environment via number of conversational turns between the child and parents. | at 6 month, 12 month, 18 month, 24 month, 3 year, and 4 year visits | 
| Changes in hearing thresholds | Hearing thresholds in dB as assessed using Conditioned Play Audiometry (CPA) or Visual Reinforced Audiometry (VRA) dependent on child age and developmental ability. | at 6 month, 12 month, 18 month, 24 month, 3 year, and 4 year visits | 
| Otoacoustic Emissions (OAEs) | Signals produced by excitation of hair cells in cochlea are measured for a range of frequencies. | At first study visit | 
| Changes in tympanometric pressure profile in the inner ear | Wide Band Tympanometry is completed to measure variability in tympanometric pressure for left and right ears that may affect hearing profile. | at 6 month, 12 month, 18 month, 24 month, 3 year, and 4 year visits | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensory profile 2 Auditory Processing subtest | parent-report measure of child's behavioral responses to sounds in their environment | at 6 month, 12 month, 18 month, 24 month, 3 year, and 4 year visits | 
| Sensory Profile 2 Attentional subtest | parent-report measure of child's awareness of and responses to sensory cues in their environment. | at 6 month, 12 month, 18 month, 24 month, 3 year, and 4 year visits |