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A clear distinction between cortico-subthalamic (hyperdirect) and cortico-tegmental projections (superolateral medial forebrain bundle, slMFB) so far is elusive. Deep Brain Stimulation (DBS) of the slMFB (for major depression, MD and obsessive compulsive disorders, OCD) has on the one hand been interpreted as actually involving limbic (prefrontal) hyperdirect pathways. On the other hand slMFB\u2019s stimulation region in the mesencephalic ventral tegmentum is said to impact on other structures too, going beyond the antidepressant (or anti OCD) efficacy of sole modulation of the cortico-tegmental reward-associated pathways. We have here used a normative diffusion MRT template (HCP, <jats:italic>n<\/jats:italic>\u2009=\u200980) for long-range tractography and augmented this dataset with ex-vivo high resolution data (<jats:italic>n<\/jats:italic>\u2009=\u20091) in a stochastic brain space. We compared this data with histological information and used the high resolution ex-vivo data set to scrutinize the mesencephalic tegmentum for small fiber pathways present. Our work resolves an existing ambiguity between slMFB and prefrontal hyperdirect pathways which\u2014for the first time\u2014are described as co-existent. DBS of the slMFB does not appear to modulate prefrontal hyperdirect cortico-subthalamic but rather cortico-tegmental projections. Smaller fiber structures in the target region\u2014as far as they can be discerned\u2014appear not to be involved in slMFB DBS. Our work enfeebles previous anatomical criticism and strengthens the position of the slMFB DBS target for its use in MD and OCD.<\/jats:p>","DOI":"10.1007\/s00429-021-02373-x","type":"journal-article","created":{"date-parts":[[2021,9,5]],"date-time":"2021-09-05T09:02:16Z","timestamp":1630832536000},"page":"23-47","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Diverging prefrontal cortex fiber connection routes to the subthalamic nucleus and the mesencephalic ventral tegmentum investigated with long range (normative) and short range (ex-vivo high resolution) 7T DTI"],"prefix":"10.1007","volume":"227","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1703-6283","authenticated-orcid":false,"given":"Volker A.","family":"Coenen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1t\u00e9 D.","family":"D\u00f6br\u00f6ssy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi Jia","family":"Teo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Wessolleck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastian E. 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He receives an ongoing collaborative grant from BrainLab (Munich, Germany). Dr. Coenen is scientific advisor for CereGate (Hamburg, Germany) and Cortec (Freiburg, Germany). Dr. Sajonz received funding from CereGate (Hamburg, Germany) without relation to this work. Dr. Reinacher receives research support from: Else Kr\u00f6ner-Fresenius Foundation and Fraunhofer Foundation (ATTRACT). He has received personal honoraria for lectures or advice and is consultant to Boston Scientific, Inomed and Brainlab. The other authors have nothing to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This paper represents a conceptual view which is only in part based on own treated patients but on the combined evaluation of a normative cohort (HCP). The imaging information therefore is not intended for surgical approaches, stimulation planning or steering which\u2014in our view\u2014should always be based on individual imaging.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclaimer"}},{"value":"The use of human brain tissue was granted by the IRB of Freiburg University under no. 203\/11.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}