Functional brainstem imaging reveals brainstem nuclei governing human baroreflex function

Abstract

Introduction: Brainstem nuclei mediate baroreflex adjustments in efferent sympathetic and parasympathetic traffic. Yet, human brainstem physiology is poorly understood given the lack of suitable methodology. We developed a novel approach combining pharmacological testing, beat-by-beat cardiovascular monitoring, and high-resolution functional magnetic resonance imaging (fMRI) to assess human baroreflex regulation at the level of the brainstem. Methods: In 10 healthy men (29.7 ± 6.9 years; 80.1 ± 9.9 kg), we monitored continuous finger arterial blood pressure and ECG using customized hardware during multiband fMRI brain acquisitions. We applied repeated intravenous phenylephrine (PHE, 25 and 75 lg, n = 8) and nitroprusside (NTP 25 and 75 lg, n = 8) boluses using a remote controlled injector. Brainstem and hypothalamus fMRI Images were analyzed to identify brainstem nuclei involved in baroreflexmediated blood pressure control using tensorial masked Independent Component Analysis (mICA). BP changes were correlated with the time-courses of blood-oxygen-level dependent (BOLD) signals by mixed-effects general linear model. Results: Pharmacological testing yielded reliable baroreflex sensitivity measurements in the MRI scanner. fMRI combined with the measurement of baroreflex-mediated changes in heart rate and blood pressure revealed nuclei regulated through baroreflex input. The strongest correlations between BOLD time-course and BP was observed in the left solitary tract (NTP: deactivation P \0.001; z-score: 6.9), the caudal ventrolateral medulla (NTP: activation, right side: P = 0.0012; z-score: 4.11, left side: P\0.001; z-score: 5.05), the rostral ventrolateral medulla (NTP: activation, right side P\ 0.001; z-score: 7.25) and in the left paraventricular nucleus (PHE: activation P \0.001; z-score: 9.00; NTP: activation P\ 0.001; z-score: 7.11). P-values were Bonferroni corrected for 60 independent components. Conclusion: We developed novel approach testing baroreflex regulation at the level of the brainstem in humans. The methodology identified baroreflex-mediated activation and deactivation Patterns consistent with previous investigations in animal models. The methodology can be applied to elucidate human physiology and mechanisms of autonomic cardiovascular disease.