{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T12:44:09Z","timestamp":1793882649794,"version":"4.7.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neural Circuits"],"abstract":"<jats:p>The substantia nigra pars compacta (SNc), one of the main dopaminergic nuclei of the brain, exerts a regulatory function on the basal ganglia circuitry via the nigro-striatal pathway but its possible dopaminergic innervation of the thalamus has been only investigated in non-human primates. The impossibility of tract-tracing studies in humans has boosted advanced MRI techniques and multi-shell high-angular resolution diffusion MRI (MS-HARDI) has promised to shed more light on the structural connectivity of subcortical structures. Here, we estimated the possible dopaminergic innervation of the human thalamus via an MS-HARDI tractography of the SNc in healthy human young adults. Two MRI data sets were serially acquired using MS-HARDI schemes from ADNI and HCP neuroimaging initiatives in a group of 10 healthy human subjects (5 males, age range: 25\u201330\u202fyears). High resolution 3D-T1 images were independently acquired to individually segment the thalamus and the SNc. Starting from whole-brain probabilistic tractography, all streamlines through the SNc reaching the thalamus were counted, separately for each hemisphere, after excluding streamlines through the substantia nigra pars reticulata and all those reaching the basal ganglia, the cerebellum and the cortex. We found a reproducible structural connectivity between the SNc and the thalamus, with an average of ~12% of the total number of streamlines encompassing the SNc and terminating in the thalamus, with no other major subcortical or cortical structures involved. The first principal component map of dopamine receptor density from a normative PET image data set suggested similar dopamine levels across SNc and thalamus. This is the first quantitative report from in-vivo measurements in humans supporting the presence of a direct nigro-thalamic dopaminergic projection. While histological validation and concurrent PET-MRI remains needed for ultimate proofing of existence, given the potential role of this pathway, the possibility to achieve a good reproducibility of these measurements in humans might enable the monitoring of dopaminergic-related disorders, towards targeted personalized therapies.<\/jats:p>","DOI":"10.3389\/fncir.2024.1522421","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T09:51:23Z","timestamp":1736416283000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Evidence for direct dopaminergic connections between substantia nigra pars compacta and thalamus in young healthy humans"],"prefix":"10.3389","volume":"18","author":[{"given":"Giovanni","family":"Cirillo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Caiazzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Franza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Cirillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Papa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.neuroscience.2006.08.033","article-title":"Substantia nigra compacta neurons that innervate the reticular thalamic nucleus in the rat also project to striatum or globus pallidus: Implications for abnormal motor behavior","volume":"143","author":"Anaya-Martinez","year":"2006","journal-title":"Neuroscience"},{"key":"ref2","doi-asserted-by":"publisher","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":"ref3","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1093\/cercor\/bhk004","article-title":"White Matter Pathway Asymmetry Underlies Functional Lateralization","volume":"17","author":"Barrick","year":"2006","journal-title":"Cereb. 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Neurobiol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1016\/j.neuroimage.2012.06.005","article-title":"Anatomically-constrained tractography: improved diffusion MRI streamlines tractography through effective use of anatomical information","volume":"62","author":"Smith","year":"2012","journal-title":"NeuroImage"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.neuroimage.2012.11.049","article-title":"SIFT: Spherical-deconvolution informed filtering of tractograms","volume":"67","author":"Smith","year":"2013","journal-title":"NeuroImage"},{"key":"ref55","author":"Tournier","year":"2010"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.neuroimage.2016.08.016","article-title":"Denoising of diffusion MRI using random matrix theory","volume":"142","author":"Veraart","year":"2016","journal-title":"NeuroImage"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cortex.2015.02.004","article-title":"Structural and functional dysconnectivity of the fronto-thalamic system in schizophrenia: a DCM-DTI study","volume":"66","author":"Wagner","year":"2015","journal-title":"Cortex"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-1-4615-1235-6_2","article-title":"Basal ganglia circuits in movementand movement disorders","volume-title":"Basal Ganglia and Thalamus in Health and Movement Disorders","author":"Wichmann","year":"2001"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.neuron.2024.01.002","article-title":"The mediodorsal thalamus in executive control","volume":"112","author":"Wolff","year":"2024","journal-title":"Neuron"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"e26653","DOI":"10.7554\/eLife.26653","article-title":"Anatomical and functional organization of the human substantia nigra and its connections","volume":"6","author":"Zhang","year":"2017","journal-title":"eLife"}],"container-title":["Frontiers in Neural Circuits"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2024.1522421\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T09:51:27Z","timestamp":1736416287000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncir.2024.1522421\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,9]]},"references-count":60,"alternative-id":["10.3389\/fncir.2024.1522421"],"URL":"https:\/\/doi.org\/10.3389\/fncir.2024.1522421","relation":{},"ISSN":["1662-5110"],"issn-type":[{"value":"1662-5110","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,9]]},"article-number":"1522421"}}