Neurochemistry as a moderator of brain networks for language and literacy learning

Investigator: Fumiko Hoeft, MD, PhD
Sponsor: Haskins Laboratories, Inc

Location(s): United States


The proposed research will provide links between neural oscillations, BOLD signal, neurochemistry, perceptual and cognitive measure, and reading ability, critical for the development of a comprehensive and mechanistic model of the neurobiological underpinnings of reading disability (RD), a life-long learning disorder that afflicts 5-10% of the Nation's children. Moreover, the proposed research will provide important foundational knowledge about biologic pathways, which may suggest pharmacological agents that can supplement and enhance effects from more conventional reading interventions.

Efficient phonological processing provides a basis for learning to read, a process that relies on successful linking of visual symbols to their corresponding speech sounds. Although the causal relationship between phonological processing, print-speech integration and fluent reading, as well as their underlying basic mechanisms are still under debate, these processes all require precise timing mechanisms. Fundamental to these timing mechanisms are two neurotransmitters, glutamate (Glu) and gama-aminobutyric acid (GABA), which play major roles in cortical excitability and the generation of slow and fast neural oscillations that correspond respectively to the rates of syllabic and phonemic rates. We have recently published the first neurochemical evidence linking elevated Glu with reading deficits using Magnetic Resonance Spectroscopy (MRS) in emergent readers. Additional preliminary studies suggest links between Glu, reading-related functional MRI activation, connectivity and trial-to-trial variability, neural oscillation and reading ability, as well as links between regionally-specific (left but not right) superior temporal GABA, neural oscillation, temporal auditory processing and reading. From these findings we propose and test a model, grounded by human and animal studies, that links elevated Glu (and Glu/GABA imbalance) to hyperexcitablity and neural noise, which manifests as one key proximal contributor of reading disability (RD) by its impact on neural oscillation, regional activation, and functional connectivity. We further posit that the compounding effects of neural noise within distributed regions on long-range regional links make integrative processes that precise timing and predictive coding mechanisms, such as multimodal integration and especially reading, particularly susceptible to excitation/inhibition imbalance. In 150 children (ages 8-9) with a wide range of reading abilities, we will examine relationships between neurochemistry, neural oscillation, functional activation, and functional connectivity (Aim 1), and how variation in these relationships predicts individual differences in sensory processing (including auditory-visual [AV] integration), and print-speech integration (Aim 2). The proposed study not only contributes to the ultimate goal of constructing a causal model of reading and RD, but also provides critical information about biological pathways potentially amenable to remediation.