Chemosensitive brainstem and diencephalic components in breath-hold fMRI

ObjectiveThe knowledge on breathing control and central chemoreception, key subcortical functions involved in several neuropathologies, is still mainly based on animal studies. In humans, functional MRI (fMRI) offers the needed spatio-temporal resolution and non-invasiveness, but the lack of specific tools and preprocessing solutions hinders its use in brainstem studies. We hereby propose an original fMRI analysis pipeline aimed at unravelling central chemoreception mechanisms, by integrating acquisition, spatial coregistration, noise removal and a novel data-driven analysis solution to compare network activation levels across tasks or conditions in fMRI. ApproachNovel analysis methodologies are integrated with the optimization of known preprocessing approaches to physiological noise correction and brainstem-focused coregistration. We couple independent components of fMRI data, separately estimated from healthy subjects during Free Breathing (FB) and Breath Hold (BH), by means of spatial correlation. We then identify statistically significant differences between BH and FB in CO2-dependent components by means of voxel-wise comparisons of components percent signal change. Components were localized using the Brainstem Navigator Atlas for enhancing network interpretability. Main ResultsUsing the pipeline we characterized CO2-related BOLD oscillations within the central control system of breathing. We corroborated the primary chemoreceptive role of medullary raphe in healthy subjects. We observed that BH over-activated ascending sensory-motor projections through the postero-lateral thalamus, descending projections through the putamen, and peripheral sensations entry points in the dorsal medulla. We highlighted the role of latero-dorsal tegmentum in the response to hypercapnia-induced aversive effects. SignificanceOur method allows to non-invasively locate primary chemoreception and related arousal triggers, characterizing alterations and therefore fostering the identification of therapeutic targets in abnormal breathing. Moreover, the proposed strategy addresses the issues of inter-task comparison among homologous independent sources, of their characterization and interpretation. Its extension could benefit all similarly challenging brainstem-focused studies, including those on Parkinsons and Alzheimers diseases.