Abstract 041: Hypoxic Peripheral Chemoreceptor Activation Engages Sympathetic Brainstem and Hypothalamic Nuclei in Human Subjects

Abstract

Peripheral carotid chemoreceptors, which raise sympathetic activation at the brainstem level, may serve as targets for antihypertensive therapy. However, human peripheral chemoreflex regulation in the brainstem is poorly understood due to lack of suitable methodologies. Therefore, we combined measurements of beat-by-beat blood pressure and SpO2, and high-resolution functional magnetic resonance imaging (fMRI) to elucidate human brainstem circuits engaged through hypoxic peripheral chemoreceptor activation. We submitted 12 healthy men (29.7 ±6.6 years; 24.0 ±1.86 kg/m2) to five hypoxic episodes by breathing 10% oxygen for 180 seconds followed by 90 seconds normoxia during multiband fMRI brain acquisitions. We monitored continuous finger arterial blood pressure using customized hardware, ECG, and SpO2. Brainstem and hypothalamus fMRI images were analyzed to identify nuclei involved in peripheral chemoreflex processing. Systolic blood pressure (SBP) and SpO2 time courses were correlated with the blood-oxygen-level dependent signals with a general linear model. With hypoxia, SpO2 decreased by 12.32 ±3.68% (p < 0.01), heart rate increased 13.86 ±3.47 bpm (p < 0.01), and SBP decreased with hypoxia 5.45 ±5.5 mmHg (p < 0.01). In the brainstem, the nucleus tractus solitarii (t-values: SpO2: 5.9; SBP: 4.79), the caudal ventrolateral medulla (SpO2: 5.61; SBP: 5.59), intermediate reticular nucleus (SpO2: 4.7, SBP: 5.98), nucleus ambiguus (SpO2: 5.03, SBP: 5.59), dorsal motor nucleus of the vagal nerve (SBP: 4.79), and inferior olive (SpO2: 4.7, SBP: 6.16) were identified with high sensitivity and corrected for multiple comparisons (p < 0.01). Furthermore, we observed activation of the following hypothalamic nuclei: paraventricular nucleus (SpO2: 7.67), anterior and lateral hypothalamic area (SpO2: 7.67, SBP: 4.79), supraoptic nucleus, and tuberomammillary nucleus (SpO2: 7.07). High-resolution brainstem fMRI during repeated hypoxia traces brainstem circuits engaged by peripheral chemoreceptors. The methodology can be applied to study peripheral chemoreceptor contributions to human cardiovascular disease and may have utility in identifying patients likely to respond to peripheral chemoreceptor modulation.