# GABA and glutamate changes underlying altered autonomic function in obstructive sleep apnea

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $728,573

## Abstract

PROJECT SUMMARY
At least 10% of the population has obstructive sleep apnea (OSA), a condition where breathing is interrupted
hundreds of times a night due to collapse of the upper airway. The disorder is accompanied by psychological
impairments and cardiovascular morbidity and mortality, but symptoms are only partially addressed with
continuous positive airway pressure (CPAP), the gold standard intervention, indicating that mechanisms other
than breathing interruptions contribute to health problems in OSA. Impaired autonomic function due to neural
alterations is a likely source of symptoms in OSA, since structural and functional deficits are present in brain
regions that regulate such functions. Symptoms are sex-specific, with females typically showing greater severity
despite lower prevalence than males. However, neuroimaging findings have not distinguished the nature of the
brain pathology. Based on structural, functional, and preliminary findings of altered neurotransmitter levels, and
animal models of OSA, we hypothesize that brain alterations impact limbic regions, and the insula in particular.
The insula plays key roles in autonomic regulation as well as mood and some cognitive functions, and there may
be reorganization that underlies altered function in the structure. Furthermore, since some symptoms do not
resolve with CPAP, the reorganization may remain even with treatment. We propose measuring neurotransmitter
levels in the insula in OSA, and relating these levels to the extent of structural and functional deficits in the
condition, with the hypothesis that the altered function is associated with altered GABA and glutamate, a theory
supported by our preliminary data. We will also test whether such changes are present with CPAP. We will use
two-dimensional magnetic resonance spectroscopy (MRS) to measure GABA and glutamate, in conjunction with
structural measures sensitive to cellular size and integrity (with diffusion tensor imaging, DTI) and water content
(free water with T2 relaxation time, and extracellular water with DTI-derived free water fraction [FW]). FW is
important since extracellular rather than intracellular glutamate leads to excitotoxicity. Function will be measured
with functional magnetic resonance imaging (fMRI) during an autonomic challenge, the Valsalva maneuver. We
will study 60 untreated, newly-diagnosed OSA, 60 matched controls, and 60 OSA patients with 1 year of
compliant CPAP use. We will assess whether GABA and glutamate in the insula are altered in OSA vs. controls,
and in treated vs. untreated patients. We will relate these neurotransmitter levels to DTI indices of tissue
structure, mean diffusivity (MD), and fractional anisotropy (FA). We will also relate levels of GABA and glutamate
to the magnitude of fMRI responses during the autonomic challenge. The findings will help explain mechanisms
of brain injury and reorganization in OSA, and suggest possible treatment options to address common symptoms
in OSA not ...

## Key facts

- **NIH application ID:** 9966021
- **Project number:** 5R01HL135562-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Paul M Macey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $728,573
- **Award type:** 5
- **Project period:** 2018-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966021

## Citation

> US National Institutes of Health, RePORTER application 9966021, GABA and glutamate changes underlying altered autonomic function in obstructive sleep apnea (5R01HL135562-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9966021. Licensed CC0.

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