The anatomy of the human medial forebrain bundle: ventral tegmental area connections to reward-associated subcortical and frontal lobe regions
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Introduction: Despite their importance in reward, motivation, and learning there is only sparse anatomical knowledge about the human medial forebrain bundle (MFB) and the connectivity of the ventral tegmental area (VTA). A thorough anatomical and microstructural description of the reward related PFC/OFC regions and their connection to the VTA - the superolateral branch of the MFB (slMFB) - is however mandatory to enable an interpretation of distinct therapeutic effects from different interventional treatment modalities in neuropsychiatric disorders (DBS, TMS etc.). This work aims at a normative description of the human MFB (and more detailed the slMFB) anatomy with respect to distant prefrontal connections and microstructural features. Methods and material: = 55; mean age ± SD, 40 ± 10 years; 32 females) underwent high resolution anatomical magnetic resonance imaging including diffusion tensor imaging. Connectivity of the VTA and the resulting slMFB were investigated on the group level using a global tractography approach. The Desikan/Killiany parceling (8 segments) of the prefrontal cortex was used to describe sub-segments of the MFB. A qualitative overlap with Brodmann areas was additionally described. Additionally, a pure visual analysis was performed comparing local and global tracking approaches for their ability to fully visualize the slMFB. Results: The MFB could be robustly described both in the present sample as well as in additional control analyses in data from the human connectome project. Most VTA- connections reached the superior frontal gyrus, the middel frontal gyrus and the lateral orbitofrontal region corresponding to Brodmann areas 10, 9, 8, 11, and 11m. The projections to these regions comprised 97% (right) and 98% (left) of the total relative fiber counts of the slMFB. Discussion: The anatomical description of the human MFB shows far reaching connectivity of VTA to reward-related subcortical and cortical prefrontal regions - but not to emotion-related regions on the medial cortical surface - realized via the superolateral branch of the MFB. Local tractography approaches appear to be inferior in showing these far-reaching projections. Since these local approaches are typically used for surgical targeting of DBS procedures, the here established detailed map might - as a normative template - guide future efforts to target deep brain stimulation of the slMFB in depression and other disorders related to dysfunction of reward and reward-associated learning.
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The superolateral branch of the medial forebrain bundle connects the ventral tegmental area to the orbitofrontal cortex and ventromedial prefrontal cortex via the ventral capsule/ventral striatum.
“The superolateral branch of the MFB connects the VTA to the OFC and vmPFC via the VC/VS [65].”
From Deep brain stimulation for depression. (2022) · cites this paper as [65]
vALIC DBS improved mood in primary OCD and was associated with enhanced striatal reward-processing and dopamine release, which may be important mechanisms for reversing anhedonia and lack of positive mood in major depression.
“DBS of the vALIC improved mood in patients with primary OCD and was associated with enhanced striatal reward-processing and dopamine release, which may be important mechanisms for the reversal of anhedonia and lack of positive mood in major depression [52,65,100,101].”
From Deep brain stimulation for depression. (2022) · cites this paper as [65]
Tractography studies in healthy individuals show that the MFB connects the VTA with the OFC and medial and dorsolateral prefrontal cortices via the VC/VS, forming a circuit involved in reward, motivation, and emotion processing.
“Tractography studies in healthy individuals have revealed that the MFB connects the ventral tegmental area (VTA) with the OFC and medial and dorsolateral prefrontal cortices via the VC/VS, together constituting a circuit involved in the processing of rewards, motivation, and emotions [65].”
From Deep brain stimulation for depression. (2022) · cites this paper as [65]
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- Authors
- Coenen, V. A., Schumacher, L. V., Kaller, C., Schlaepfer, T. E., Reinacher, P. C., Egger, K., Urbach, H., & Reisert, M.
- Affiliations
- University of Freiburg (DE)
- Corresponding author
- Coenen, Volker Arnd
- ORCID
- Venue
- NeuroImage Clinical
- Publisher
- Elsevier BV
- Published
- 2018
- Volume
- 18
- Pages
- 770-783
- ISSN
- 2213-1582 (ISSN-L)
- PMC
- PMC5964495
- OpenAlex
- W2791876368
- Cited by
- 127
- References
- 66
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 16 · 2023: 17 · 2022: 17 · 2021: 19 · 2020: 19 · 2019: 9 · 2018: 5
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- NeuroImage Clinical (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke
- National Institute of Dental and Craniofacial Research
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- medial forebrain bundle, ventral tegmental area, reward systems, orbitofrontal cortex, superior frontal gyrus, middle frontal gyrus, depression, diffusion tensor imaging, Human Connectome Project, Brodmann areas
- MeSH terms
- Adult, Female, Frontal Lobe, Humans, Magnetic Resonance Imaging, Male, Medial Forebrain Bundle, Middle Aged, Prefrontal Cortex, Ventral Tegmental Area, Deep Brain Stimulation, Diffusion Tensor Imaging
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