{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:12:49Z","timestamp":1792203169732,"version":"4.4.0"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T00:00:00Z","timestamp":1743379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Olfaction is in many ways the least understood sensory modality. Its organization and connectivity are still under debate. The aim of this study was to investigate the anatomy of the olfactory system by using a cadaver fiber dissection technique and in vivo tractography to attain a deeper understanding of the subcortical connectivity and organization. Methods: Ten cerebral hemispheres were used in this study for white matter dissection according to Klingler\u2019s technique. Measurements of different cortical structures and interhemispheric symmetry were compared. Diffusion tensor imaging sequences from twenty-five healthy individuals from the Human Connectome Project dataset were used to explore the connectivity of the olfactory system using DSI Studio. White matter connectivity between the following were reconstructed in vivo: (1) Olfactory bulb to primary olfactory cortices; (2) Olfactory bulb to secondary olfactory cortices; (3) Primary to secondary olfactory cortices. The DTI metrics of the identified major associative, projection and commissural pathways were subsequently correlated with olfactory function and cognition in seventy-five healthy individuals with Spearman\u2019s rank correlation and the Benjamini\u2013Hochberg method for false discoveries (CI 95%, p &lt; 0.05) using R. Results: 1. The dissection showed that the lateral stria was significantly longer on the left side and projected towards the amygdala, the entorhinal and piriform cortex. 2. The medial stria was not evident as a consistent white matter structure. 3. Both dissection and tractography showed that major associative white matter pathways such as the uncinate fasciculus, the inferior fronto-occipital fasciculus and cingulum supported the connectivity between olfactory areas together with the anterior commissure. 4. No significant correlation was found between DTI metrics and sensory or cognition test results. Conclusions: We present the first combined fiber dissection analysis and tractography of the olfactory system. We propose a novel definition where the primary olfactory network is defined by the olfactory tract\/bulb and primary olfactory cortices through the lateral stria only. The uncinate fasciculus, inferior fronto-occipital fasciculus and cingulum are the associative pathways supporting the connectivity between primary and secondary olfactory areas together with the anterior commissure. We suggest considering these structures as a secondary olfactory network. Further work is needed to attain a deeper understanding of the pathological and physiological implications of the olfactory system.<\/jats:p>","DOI":"10.3390\/brainsci15040368","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T11:17:57Z","timestamp":1743506277000},"page":"368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The Bulb, the Brain and the Being: New Insights into Olfactory System Anatomy, Organization and Connectivity"],"prefix":"10.3390","volume":"15","author":[{"given":"Anton","family":"Stenwall","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aino-Linnea","family":"Uggla","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Weibust","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Fahlstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine, Uppsala University, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2869-2873","authenticated-orcid":false,"given":"Mats","family":"Ryttlefors","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4702-526X","authenticated-orcid":false,"given":"Francesco","family":"Latini","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,31]]},"reference":[{"key":"ref_1","first-page":"B5428","article-title":"Testing olfactory function and mapping the structural olfactory networks in the brain","volume":"65","year":"2018","journal-title":"Dan. Med. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/B978-0-444-63855-7.00002-2","article-title":"Anatomy of the olfactory system","volume":"164","author":"Smith","year":"2019","journal-title":"Handb. Clin. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/chemse\/bjt072","article-title":"Olfactory disorders and quality of life\u2014An updated review","volume":"39","author":"Croy","year":"2014","journal-title":"Chem. Senses"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/chemse\/bjp083","article-title":"An initial evaluation of the functions of human olfaction","volume":"35","author":"Stevenson","year":"2010","journal-title":"Chem. Senses"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1146\/annurev-psych-042023-101155","article-title":"What Does the Human Olfactory System Do, and How Does It Do It?","volume":"75","author":"Gottfried","year":"2024","journal-title":"Annu. Rev. Psychol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eadn3028","DOI":"10.1126\/sciadv.adn3028","article-title":"Nature and human well-being: The olfactory pathway","volume":"10","author":"Bratman","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1037\/neu0000439","article-title":"Contrasting olfaction, vision, and audition as predictors of cognitive change and impairment in non-demented older adults","volume":"32","author":"MacDonald","year":"2018","journal-title":"Neuropsychology"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Croy, I., Springborn, M., L\u00f6tsch, J., Johnston, A.N.B., and Hummel, T. (2011). Agreeable smellers and sensitive neurotics--correlations among personality traits and sensory thresholds. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018701"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1146\/annurev-physiol-031820-092824","article-title":"Olfactory Circuitry and Behavioral Decisions","volume":"83","author":"Mori","year":"2021","journal-title":"Annu. Rev. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1467-6494.1992.tb00970.x","article-title":"An introduction to the five-factor model and its applications","volume":"60","author":"McCrae","year":"1992","journal-title":"J. Pers."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rochet, M., El-Hage, W., Richa, S., Kazour, F., and Atanasova, B. (2018). Depression, Olfaction, and Quality of Life: A Mutual Relationship. Brain Sci., 8.","DOI":"10.3390\/brainsci8050080"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s11065-022-09573-0","article-title":"Does Olfactory Training Improve Brain Function and Cognition? A Systematic Review","volume":"34","author":"Vance","year":"2024","journal-title":"Neuropsychol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.neurad.2021.04.035","article-title":"Reorganizing brain structure through olfactory training in post-traumatic smell impairment: An MRI study","volume":"49","author":"Rezaeyan","year":"2022","journal-title":"J. Neuroradiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Milardi, D., Cacciola, A., Calamuneri, A., Ghilardi, M.F., Caminiti, F., Cascio, F., Andronaco, V., Anastasi, G., Mormina, E., and Arrigo, A. (2017). The Olfactory System Revealed: Non-Invasive Mapping by using Constrained Spherical Deconvolution Tractography in Healthy Humans. Front. Neuroanat., 11.","DOI":"10.3389\/fnana.2017.00032"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.neunet.2009.07.013","article-title":"Glomerular microcircuits in the olfactory bulb","volume":"22","author":"Linster","year":"2009","journal-title":"Neural Netw."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/B978-0-444-63855-7.00006-X","article-title":"Central olfactory structures","volume":"164","author":"Cleland","year":"2019","journal-title":"Handb. Clin. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/ca.22338","article-title":"Olfaction: Anatomy, physiology, and disease","volume":"27","author":"Patel","year":"2014","journal-title":"Clin. Anat. N. Y."},{"key":"ref_18","first-page":"481","article-title":"The secondary olfactory areas in the human brain","volume":"88","author":"Allison","year":"1954","journal-title":"J. Anat."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"939","DOI":"10.4067\/S0717-95022011000300047","article-title":"Comparative Morphometry of the Olfactory Bulb, Tract and Stria in the Human, Dog and Goat","volume":"29","author":"Kavoi","year":"2011","journal-title":"Int. J. Morphol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/ca.23003","article-title":"Anatomy of the olfactory nerve: A comprehensive review with cadaveric dissection","volume":"31","author":"Campero","year":"2018","journal-title":"Clin. Anat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1002\/hbm.25741","article-title":"Olfactory loss and brain connectivity after COVID-19","volume":"43","author":"Esposito","year":"2022","journal-title":"Hum. Brain Mapp."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jneumeth.2015.06.019","article-title":"The use of a cerebral perfusion and immersion-fixation process for subsequent white matter dissection","volume":"253","author":"Latini","year":"2015","journal-title":"J. Neurosci. Methods"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1016\/j.neuroimage.2012.02.018","article-title":"The Human Connectome Project: A data acquisition perspective","volume":"62","author":"Ugurbil","year":"2012","journal-title":"NeuroImage"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.neuroimage.2015.10.019","article-title":"An integrated approach to correction for off-resonance effects and subject movement in diffusion MR imaging","volume":"125","author":"Andersson","year":"2016","journal-title":"NeuroImage"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/S1053-8119(03)00336-7","article-title":"How to correct susceptibility distortions in spin-echo echo-planar images: Application to diffusion tensor imaging","volume":"20","author":"Andersson","year":"2003","journal-title":"NeuroImage"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1002\/mrm.24623","article-title":"Effects of image reconstruction on fiber orientation mapping from multichannel diffusion MRI: Reducing the noise floor using SENSE","volume":"70","author":"Sotiropoulos","year":"2013","journal-title":"Magn. Reson. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e80713","DOI":"10.1371\/journal.pone.0080713","article-title":"Deterministic diffusion fiber tracking improved by quantitative anisotropy","volume":"8","author":"Yeh","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Panesar, S.S., Yeh, F.-C., Jacquesson, T., Hula, W., and Fernandez-Miranda, J.C. (2018). A Quantitative Tractography Study Into the Connectivity, Segmentation and Laterality of the Human Inferior Longitudinal Fasciculus. Front. Neuroanat., 12.","DOI":"10.3389\/fnana.2018.00047"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/nrn756","article-title":"The problem of functional localization in the human brain","volume":"3","author":"Brett","year":"2002","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"118274","DOI":"10.1016\/j.neuroimage.2021.118274","article-title":"Myelo- and cytoarchitectonic microstructural and functional human cortical atlases reconstructed in common MRI space","volume":"239","author":"Pijnenburg","year":"2021","journal-title":"NeuroImage"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Latini, F., Fahlstr\u00f6m, M., Berntsson, S.G., Larsson, E.-M., Smits, A., and Ryttlefors, M. (2019). A novel radiological classification system for cerebral gliomas: The Brain-Grid. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211243"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.brainres.2017.09.005","article-title":"Segmentation of the inferior longitudinal fasciculus in the human brain: A white matter dissection and diffusion tensor tractography study","volume":"1675","author":"Latini","year":"2017","journal-title":"Brain Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/nrn2883","article-title":"Central mechanisms of odour object perception","volume":"11","author":"Gottfried","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_34","unstructured":"Menini, A. (2010). Cortical Activity Evoked by Odors. The Neurobiology of Olfaction, CRC Press\/Taylor & Francis. Frontiers in Neuroscience."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Van Hartevelt, T.J., and Kringelbach, M.L. (2012). The Olfactory System. The Human Nervous System, Elsevier.","DOI":"10.1016\/B978-0-12-374236-0.10034-3"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0924-8196(99)80023-2","article-title":"The human basal forebrain. Part I. An overview","volume":"Volume 15","author":"Sakamoto","year":"1999","journal-title":"Handbook of Chemical Neuroanatomy"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Price, J.L. (2009). Olfactory Higher Centers Anatomy. Encyclopedia of Neuroscience, Elsevier.","DOI":"10.1016\/B978-008045046-9.01692-2"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1093\/brain\/awt094","article-title":"Dissecting the uncinate fasciculus: Disorders, controversies and a hypothesis","volume":"136","author":"Skipper","year":"2013","journal-title":"Brain J. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ebcr.2014.07.002","article-title":"Olfactory auras caused by a very focal isolated epileptic network in the amygdala","volume":"2","author":"Hamasaki","year":"2014","journal-title":"Epilepsy Behav. Case Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Dahmani, L., Courcot, B., Near, J., Patel, R., Amaral, R.S.C., Chakravarty, M.M., and Bohbot, V.D. (2019). Fimbria-Fornix Volume Is Associated With Spatial Memory and Olfactory Identification in Humans. Front. Syst. Neurosci., 13.","DOI":"10.3389\/fnsys.2019.00087"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1007\/s11682-017-9781-0","article-title":"Exploring white matter microstructure and olfaction dysfunction in early parkinson disease: Diffusion MRI reveals new insight","volume":"13","author":"Sobhani","year":"2019","journal-title":"Brain Imaging Behav."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.bbr.2013.02.025","article-title":"Neuroanatomical correlates of olfactory loss in normal aged subjects","volume":"246","author":"Segura","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref_43","first-page":"605","article-title":"The inferior fronto-occipital fascicle: A century of controversies from anatomy theaters to operative neurosurgery","volume":"65","author":"Marras","year":"2021","journal-title":"J. Neurosurg. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/360339a0","article-title":"Functional localization and lateralization of human olfactory cortex","volume":"360","author":"Zatorre","year":"1992","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Courtiol, E., and Wilson, D.A. (2015). The olfactory thalamus: Unanswered questions about the role of the mediodorsal thalamic nucleus in olfaction. Front. Neural Circuits, 9.","DOI":"10.3389\/fncir.2015.00049"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Woo, C.C., Miranda, B., Sathishkumar, M., Dehkordi-Vakil, F., Yassa, M.A., and Leon, M. (2023). Overnight olfactory enrichment using an odorant diffuser improves memory and modifies the uncinate fasciculus in older adults. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1200448"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/4\/368\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:07:01Z","timestamp":1760029621000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/15\/4\/368"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,31]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["brainsci15040368"],"URL":"https:\/\/doi.org\/10.3390\/brainsci15040368","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,31]]}}}