Functional connectivity changes after 28 days of head-down tilt bedrest

Abstract

Introduction: Both, returning astronauts and bedridden patients, often experience orthostatic intolerance. Since cardiovascular deconditioning alone cannot explain the severity of the symptoms, we hypothesized contributory neural changes in the baroreflex circuitry. We tested this hypothesis using functional magnetic resonance imaging (fMRI) during an orthostatic challenge following head-down tilt bedrest. Methods: 47 healthy individuals (20 women; 34.7±8.8 years; 23.6±2.6 kg/m2) underwent 30 days of strict head-down tilt bedrest. They were assigned to one of four intervention groups: lower body negative pressure (LBNP) (6 h/d; n=12), sitting (6 h/d; n=11), supine cycling (1 h/d) followed by venous thigh occlusion (6 h/d; n=12), and a negative control (n=12). All underwent orthostatic tolerance testing through combined head-up tilt and LBNP. At baseline, at day 28 of bedrest, and 4 days into recovery, we acquired fMRI measurements using a 3T scanner during three different LBNP conditions (without, -10 mmHg, -30 mmHg). We determined changes in functional connectivity by applying independent component analysis followed by a dual regression using an F-test and post-hoc two-sample t-tests. Results: In all groups, orthostatic tolerance substantially decreased albeit to various degrees. We observed significant functional connectivity changes within the hypothalamus and the medulla oblongata after 28 days of bedrest. In the hypothalamus, they comprised intrinsic connectivity increases within the supraoptic, the dorsomedial, and the tuberomamillary nuclei. Moreover, the dorsomedial hypothalamic nucleus increased its connectivity to the ventromedial, and the supraoptic hypothalamic nuclei. Within the brainstem, we observed an intrinsic connectivity decrease within the rostral ventrolateral medulla, together with a connectivity increase between the raphe pallidus and the inferior olivary nuclei. There were also functional connectivity changes between hypothalamic and cortical regions. The anterior hypothalamic area and the ventromedial hypothalamic nucleus increased their connectivity to the visual cortex after 28 days of bedrest. Conclusion: Worsened orthostatic tolerance following head-down tilt bedrest, was associated with significant functional connectivity changes in hypothalamic autonomic regions, as well as in medullary nuclei regulating sympathetic efferent activity. Moreover, there were connectivity changes between hypothalamic and cortical regions. We speculate that neuroplasticity may contribute to changes in cardiovascular regulation and orthostatic intolerance after real or simulated weightlessness.