Project Summary/Abstract The purpose of this research grant application is to expand a pilot project evaluating the earliest markers of brain and pre-speech development in infants with isolated cleft of the lip and/or palate (iCL/P) – before their first exposure to anesthesia. Research has documented a high incidence of specific learning disabilities (most notably language or reading deficits) among this population. These disabilities, while not in the range of Intellectual Dysfunction, do result in academic achievement problems and lower rates of college attendance. Recent work has also documented differences in brain structure and function among people with an isolated oral cleft that is correlated to measures of cognitive and academic functioning. These differences have been identified across child, adolescent, young adult, and adult samples. Current theories on the etiology of these structural and functional differences have proposed: 1) early exposure to anesthesia, 2) obstructed airway and resulting reduced oxygenation, and 3) abnormal neural migration as potential contributing factors. The PI conducted a pilot study, obtaining structural MRI scans and vocal recording in infants with (n = 4; 2 with successful MRI) and without (n = 4) isolated oral clefts at 2 months of age (prior to any exposure to anesthesia). Results demonstrated a trend of reduced volume of myelinated white matter and reduced vocal complexity (pre-speech marker of language development) in infants with iCL/P compared to unaffected controls. While preliminary, these findings suggest that differences in infants with iCL/P may be present shortly after birth and prior to exposure to anesthesia – supporting a stronger role of genetics and development in the progression of structural and functional differences identified later in life. The proposed study will expand the pilot by recruiting a larger sample from two sites, obtaining vocal and neuronal measures at three different time points (before and after surgery for those with iCL/P), utilizing both MRI and functional near-infrared spectroscopy (fNIRS) for neural measurement, and obtaining measures of oxygenation. Specific goals of the current project are to: 1) Assess the effects of cleft presence and sex (as well as their interaction) and oxygen level on brain structure/function and pre-speech/language measures at each time point; 2) Evaluate the relationship of early brain structure/function to later brain function and language outcomes; and 3) Assess the potential impact of exposure to anesthesia on developmental trajectories within groups (i.e., iCL, iCP, iCLP, and Unaffected). The results of this study will significantly contribute to the understanding of neuronal development in infants with iCL/P and the impact of exposure to anesthesia and reduced oxygenation have on this development.

Project Narrative High incidence of language/reading issues and differential brain structure has been reported within the isolated cleft population and is proposed to be related to either: exposure to anesthesia, airway obstruction (and resulting low oxygen), or abnormal neural migration. Research on infants with and without iCL/P infancy can help evaluate the earliest markers of speech/language development and brain structure/function in relation to these possible clinical factors. Findings will provide needed information on the impact of anesthesia exposure and the risk of unidentified low oxygen due to airway obstruction on the developing brain and guide early treatment.