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Respir Physiol Neurobiol. 2014 Dec 1;204:78-85. doi: 10.1016/j.resp.2014.09.005. Epub 2014 Sep 27.

The time-course of cortico-limbic neural responses to air hunger.

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Department of Biomedical Sciences, University of South Carolina School of Medicine, Greenville, SC, USA.
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address:
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK.
Harvard Medical School, Boston, MA, USA; Division Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.


Several studies have mapped brain regions associated with acute dyspnea perception. However, the time-course of brain activity during sustained dyspnea is unknown. Our objective was to determine the time-course of neural activity when dyspnea is sustained. Eight healthy subjects underwent brain blood oxygen level dependent functional magnetic imaging (BOLD-fMRI) during mechanical ventilation with constant mild hypercapnia (∼ 45 mm Hg). Subjects rated dyspnea (air hunger) via visual analog scale (VAS). Tidal volume (V(T)) was alternated every 90 s between high VT (0.96 ± 0.23 L) that provided respiratory comfort (12 ± 6% full scale) and low V(T) (0.48 ± 0.08 L) which evoked air hunger (56 ± 11% full scale). BOLD signal was extracted from a priori brain regions and combined with VAS data to determine air hunger related neural time-course. Air hunger onset was associated with BOLD signal increases that followed two distinct temporal profiles within sub-regions of the anterior insula, anterior cingulate and prefrontal cortices (cortico-limbic circuitry): (1) fast, BOLD signal peak <30s and (2) slow, BOLD signal peak >40s. BOLD signal during air hunger offset followed fast and slow temporal profiles symmetrical, but inverse (signal decreases) to the time-courses of air hunger onset. We conclude that differential cortico-limbic circuit elements have unique contributions to dyspnea sensation over time. We suggest that previously unidentified sub-regions are responsible for either the acute awareness or maintenance of dyspnea. These data enhance interpretation of previous studies and inform hypotheses for future dyspnea research.


Air hunger; Dyspnea; Insula; Limbic; Time-course; fMRI

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