Besides being responsible for olfaction and air intake, the nose contains abundant vasculature and autonomic nervous system innervations, and it is a cerebrospinal fluid clearance site. Therefore, the nose is an attractive target for functional MRI (fMRI). Yet, nose fMRI has not been possible so far due to signal losses originating from nasal air-tissue interfaces. Here, we demonstrated feasibility of nose fMRI by using novel ultrashort/zero echo time (TE) MRI. Results obtained in the resting-state from 13 healthy participants at 7T and in 5 awake mice at 9.4T revealed a highly reproducible resting-state nose functional network that likely reflects autonomic nervous system activity. Another network observed in humans involves the nose, major brain vessels and CSF spaces, presenting a temporal dynamic that correlates with heart rate and breathing rate. These resting-state nose functional signals should help elucidate peripheral and central nervous system integrations.

A 1 Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio Finland

Department of Radiology and Biomedical Imaging Magnetic Resonance Research Center Yale University New Haven CT US

Department of Radiology Center for Magnetic Resonance Research University of Minnesota Minneapolis MN USA

Division of Biostatistics School of Public Health University of Minnesota Minneapolis MN USA

Neurology General University Hospital Charles University Prague Czech Republic

See more in PubMed

Khonsary, S. A. in Surg. Neurol. Int.7 (2016). (Copyright: © 2016 Surgical Neurology International.

Lochhead, J. J. & Thorne, R. G. Intranasal delivery of biologics to the central nervous system. Adv. Drug Deliv Rev.64, 614–628. 10.1016/j.addr.2011.11.002 (2012). PubMed

Sarin, S., Undem, B., Sanico, A. & Togias, A. The role of the nervous system in rhinitis. J. Allergy Clin. Immunol.118, 999–1016. 10.1016/j.jaci.2006.09.013 (2006). PubMed

Smith, D. H., Brook, C. D., Virani, S. & Platt, M. P. The inferior turbinate: An autonomic organ. Am. J. Otolaryngol.39, 771–775. 10.1016/j.amjoto.2018.08.009 (2018). PubMed

Wang, X. Y., Han, Y. Y., Li, G. & Zhang, B. Association between autonomic dysfunction and olfactory dysfunction in Parkinson’s disease in southern Chinese. BMC Neurol.19, 17. 10.1186/s12883-019-1243-4 (2019). PubMed PMC

Lee, P. H., Yeo, S. H., Kim, H. J. & Youm, H. Y. Correlation between cardiac 123I-MIBG and odor identification in patients with Parkinson’s disease and multiple system atrophy. Mov. Disord. 21, 1975–1977. 10.1002/mds.21083 (2006). PubMed

Goldstein, D. S. & Sewell, L. Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases. Parkinsonism Relat. Disord. 15, 516–520. 10.1016/j.parkreldis.2008.12.009 (2009). PubMed PMC

Son, G. et al. Olfactory neuropathology in Alzheimer’s disease: a sign of ongoing neurodegeneration. BMB Rep.54, 295–304. 10.5483/BMBRep.2021.54.6.055 (2021). PubMed PMC

Schubert, C. R. et al. Olfaction and the 5-year incidence of cognitive impairment in an epidemiological study of older adults. J. Am. Geriatr. Soc.56, 1517–1521. 10.1111/j.1532-5415.2008.01826.x (2008). PubMed PMC

Doty, R. L. The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann. Neurol.63, 7–15. 10.1002/ana.21327 (2008). PubMed

Ogawa, S. et al. Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. Proc. Natl. Acad. Sci. U S A. 89, 5951–5955. 10.1073/pnas.89.13.5951 (1992). PubMed PMC

Farzaneh, F., Riederer, S. J. & Pelc, N. J. Analysis of T2 limitations and off-resonance effects on spatial resolution and artifacts in echo-planar imaging. Magn. Reson. Med.14, 123–139. 10.1002/mrm.1910140112 (1990). PubMed

Jezzard, P. & Balaban, R. S. Correction for geometric distortion in echo planar images from B0 field variations. Magn. Reson. Med.34, 65–73. 10.1002/mrm.1910340111 (1995). PubMed

Andersson, J. L., Skare, S. & Ashburner, J. How to correct susceptibility distortions in spin-echo echo-planar images: application to diffusion tensor imaging. Neuroimage. 20, 870–888. 10.1016/S1053-8119(03)00336-7 (2003). PubMed

Bracher, A. K. et al. Feasibility of ultra-short echo time (UTE) magnetic resonance imaging for identification of carious lesions. Magn. Reson. Med.66, 538–545. 10.1002/mrm.22828 (2011). PubMed

Gatehouse, P. D. & Bydder, G. M. Magnetic resonance imaging of short T2 components in tissue. Clin. Radiol.58, 1–19. 10.1053/crad.2003.1157 (2003). PubMed

Bergin, C. J., Pauly, J. M. & Macovski, A. Lung parenchyma: projection reconstruction MR imaging. Radiology. 179, 777–781. 10.1148/radiology.179.3.2027991 (1991). PubMed

Weiger, M., Pruessmann, K. P. & Hennel, F. MRI with zero echo time: hard versus sweep pulse excitation. Magn. Reson. Med.66, 379–389. 10.1002/mrm.22799 (2011). PubMed

Idiyatullin, D., Corum, C., Park, J. Y. & Garwood, M. Fast and quiet MRI using a swept radiofrequency. J. Magn. Reson.181, 342–349. 10.1016/j.jmr.2006.05.014 (2006). PubMed

Idiyatullin, D., Corum, C. A., Garwood, M. & Multi-Band, S. W. I. F. T. J. Magn. Reson.251, 19–25 10.1016/j.jmr.2014.11.014 (2015). PubMed PMC

Lehto, L. J. et al. MB-SWIFT functional MRI during deep brain stimulation in rats. Neuroimage. 159, 443–448. 10.1016/j.neuroimage.2017.08.012 (2017). PubMed PMC

Paasonen, J. et al. Whole-brain studies of spontaneous behavior in head-fixed rats enabled by zero echo time MB-SWIFT fMRI. Neuroimage. 250, 118924. 10.1016/j.neuroimage.2022.118924 (2022). PubMed PMC

Kim, M. J., Jahng, G. H., Lee, S. Y. & Ryu, C. W. Functional magnetic resonance imaging with an ultrashort echo time. Med. Phys.40, 022301. 10.1118/1.4773035 (2013). PubMed

Mangia, S. et al. S. in International Society of Magnetic Resonance in Medicine.

Glover, G. H., Li, T. Q. & Ress, D. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn. Reson. Med.44, 162–167. https://doi.org/10.1002/1522-2594(200007)44:1<162::aid-mrm23>3.0.co;2-e (2000). PubMed

Werntz, D. A. & Bickford, R. G. Shannahoff-Khalsa, D. Selective hemispheric stimulation by unilateral forced nostril breathing. Hum. Neurobiol.6, 165–171 (1987). PubMed

Price, A. & Eccles, R. Nasal airflow and brain activity: is there a link? J. Laryngol Otol. 130, 794–799. 10.1017/S0022215116008537 (2016). PubMed

Shannahoff-Khalsa, D. S., Boyle, M. R. & Buebel, M. E. The effects of unilateral forced nostril breathing on cognition. Int. J. Neurosci.57, 239–249. 10.3109/00207459109150697 (1991). PubMed

Gureviciene, I. et al. Orientation selective stimulation with tetrahedral electrodes of the rat infralimbic cortex to indirectly target the amygdala. Front. Neurosci.17, 1147547. 10.3389/fnins.2023.1147547 (2023). PubMed PMC

Laakso, H. et al. Spinal cord fMRI with MB-SWIFT for assessing epidural spinal cord stimulation in rats. Magn. Reson. Med.86, 2137–2145. 10.1002/mrm.28844 (2021). PubMed PMC

Lehto, L. J. et al. Orientation selective deep brain stimulation of the subthalamic nucleus in rats. Neuroimage. 213, 116750. 10.1016/j.neuroimage.2020.116750 (2020). PubMed PMC

Lehto, L. J. et al. Tuning Neuromodulation Effects by Orientation Selective Deep Brain Stimulation in the Rat Medial Frontal Cortex. Front. Neurosci.12, 899. 10.3389/fnins.2018.00899 (2018). PubMed PMC

Wu, L. et al. Orientation selective DBS of entorhinal cortex and medial septal nucleus modulates activity of rat brain areas involved in memory and cognition. Sci. Rep.12, 8565. 10.1038/s41598-022-12383-2 (2022). PubMed PMC

Paasonen, J. et al. Multi-band SWIFT enables quiet and artefact-free EEG-fMRI and awake fMRI studies in rat. Neuroimage. 206, 116338. 10.1016/j.neuroimage.2019.116338 (2020). PubMed PMC

Raichle, M. E. The brain’s default mode network. Annu. Rev. Neurosci.38, 433–447. 10.1146/annurev-neuro-071013-014030 (2015). PubMed

Shaffer, F. & Ginsberg, J. P. An Overview of Heart Rate Variability Metrics and Norms. Front. Public. Health. 5, 258. 10.3389/fpubh.2017.00258 (2017). PubMed PMC

Low, P. A. Autonomic nervous system function. J. Clin. Neurophysiol.10, 14–27. 10.1097/00004691-199301000-00003 (1993). PubMed

Williams, M. R. & Eccles, R. The nasal cycle and age. Acta Otolaryngol.135, 831–834. 10.3109/00016489.2015.1028592 (2015). PubMed

Stoksted, P. & Thomsen, K. A. Changes in the nasal cycle under stellate ganglion block. Acta Otolaryngol. Suppl.109, 176–181. 10.3109/00016485309132517 (1953). PubMed

Bamford, O. S. & Eccles, R. The central reciprocal control of nasal vasomotor oscillations. Pflugers Arch.394, 139–143. 10.1007/BF00582915 (1982). PubMed

Bojsen-Moller, F. & Fahrenkrug, J. Nasal swell-bodies and cyclic changes in the air passage of the rat and rabbit nose. J. Anat.110, 25–37 (1971). PubMed PMC

Parthasarathy, K. & Bhalla, U. S. Laterality and symmetry in rat olfactory behavior and in physiology of olfactory input. J. Neurosci.33, 5750–5760. 10.1523/JNEUROSCI.1781-12.2013 (2013). PubMed PMC

Piechnik, S. K., Evans, J., Bary, L. H., Wise, R. G. & Jezzard, P. Functional changes in CSF volume estimated using measurement of water T2 relaxation. Magn. Reson. Med.61, 579–586. 10.1002/mrm.21897 (2009). PubMed

Williams, S. D. et al. Neural activity induced by sensory stimulation can drive large-scale cerebrospinal fluid flow during wakefulness in humans. PLoS Biol.21, e3002035. 10.1371/journal.pbio.3002035 (2023). PubMed PMC

Fultz, N. E. et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 366, 628–631. 10.1126/science.aax5440 (2019). PubMed PMC

Mestre, H. et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat. Commun.9, 4878. 10.1038/s41467-018-07318-3 (2018). PubMed PMC

Mehta, N. H. et al. The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans. Front. Physiol.12, 769948. 10.3389/fphys.2021.769948 (2021). PubMed PMC

de Leon, M. J. et al. Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. J. Nucl. Med.58, 1471–1476. 10.2967/jnumed.116.187211 (2017). PubMed PMC

Sass, L. R. et al. Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients. Fluids Barriers CNS. 17, 4. 10.1186/s12987-019-0164-3 (2020). PubMed PMC

de Leon, M. J. et al. Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment. Neurosci. Lett.333, 183–186. 10.1016/s0304-3940(02)01038-8 (2002). PubMed

Benveniste, H. et al. Glymphatic Cerebrospinal Fluid and Solute Transport Quantified by MRI and PET Imaging. Neuroscience. 474, 63–79. 10.1016/j.neuroscience.2020.11.014 (2021). PubMed PMC

Li, J. et al. Whole-brain mapping of mouse CSF flow via HEAP-METRIC phase-contrast MRI. Magn. Reson. Med.87, 2851–2861. 10.1002/mrm.29179 (2022). PubMed PMC

Zygmunt, A. & Stanczyk, J. Methods of evaluation of autonomic nervous system function. Arch. Med. Sci.6, 11–18. 10.5114/aoms.2010.13500 (2010). PubMed PMC

Marques, J. P. et al. MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field. Neuroimage. 49, 1271–1281. 10.1016/j.neuroimage.2009.10.002 (2010). PubMed

Vest, A. N. et al. An open source benchmarked toolbox for cardiovascular waveform and interval analysis. Physiol. Meas.39, 105004. 10.1088/1361-6579/aae021 (2018). PubMed PMC

Kassinopoulos, M., Harper, R. M., Guye, M., Lemieux, L. & Diehl, B. Altered Relationship Between Heart Rate Variability and fMRI-Based Functional Connectivity in People With Epilepsy. Front. Neurol.12, 671890. 10.3389/fneur.2021.671890 (2021). PubMed PMC

O’Brien, K. R. et al. Robust T1-weighted structural brain imaging and morphometry at 7T using MP2RAGE. PLoS One. 9, e99676. 10.1371/journal.pone.0099676 (2014). PubMed PMC

Jenkinson, M., Bannister, P., Brady, M. & Smith, S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage. 17, 825–841. 10.1016/s1053-8119(02)91132-8 (2002). PubMed

Hyvarinen, A. Blind source separation by nonstationarity of variance: a cumulant-based approach. IEEE Trans. Neural Netw.12, 1471–1474. 10.1109/72.963782 (2001). PubMed

Esposito, F. et al. Independent component analysis of fMRI group studies by self-organizing clustering. Neuroimage. 25, 193–205. 10.1016/j.neuroimage.2004.10.042 (2005). PubMed

Beck, A., Teboulle, M. A. Fast Iterative Shrinkage-Thresholding Algorithm for Linear Inverse Problems. SIAM J. Imaging Sci.2, 183–202. 10.1137/080716542 (2009).

Koster, J. & Rahmann, S. Snakemake–a scalable bioinformatics workflow engine. Bioinformatics. 28, 2520–2522. 10.1093/bioinformatics/bts480 (2012). PubMed

Avants, B. B., Epstein, C. L., Grossman, M. & Gee, J. C. Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med. Image Anal.12, 26–41. 10.1016/j.media.2007.06.004 (2008). PubMed PMC

Avants, B. B., Tustison, N. & Song, G. Advanced Normalization Tools: V1.0. Insight J.2, 1–35. 10.54294/uvnhin (2009).