Tomographic tract tracing and data driven approaches to unravel complex 3D fiber anatomy of DBS relevant prefrontal projections to the diencephalic-mesencephalic junction in the marmoset

Volker A Coenen; Akiya Watakabe; Henrik Skibbe; Tetsuo Yamamori; Máté D Döbrössy; Bastian E A Sajonz; Peter C Reinacher; Marco Reisert

doi:10.1016/j.brs.2023.03.012

Tomographic tract tracing and data driven approaches to unravel complex 3D fiber anatomy of DBS relevant prefrontal projections to the diencephalic-mesencephalic junction in the marmoset

Brain Stimul. 2023 Mar-Apr;16(2):670-681. doi: 10.1016/j.brs.2023.03.012. Epub 2023 Apr 6.

Authors

Volker A Coenen¹, Akiya Watakabe², Henrik Skibbe³, Tetsuo Yamamori², Máté D Döbrössy⁴, Bastian E A Sajonz⁵, Peter C Reinacher⁶, Marco Reisert⁷

Affiliations

¹ Department of Stereotactic and Functional Neurosurgery, Medical Center of the University of Freiburg, Freiburg, Germany, Breisacher Straße 64, 79106, Freiburg Im Breisgau, Germany; Medical Faculty of the University of Freiburg, Breisacher Str. 153, 79110, Freiburg Im Breisgau, Germany; Center for Deep Brain Stimulation, Medical Center of the University of Freiburg, Germany; AG Stereotaxy and Interventional Neurosciences (SIN), Department of Stereotactic and Functional Neurosurgery, Medical Center of the University of Freiburg, Freiburg, Germany, Breisacher Straße 64, 79106, Freiburg Im Breisgau, Germany.
² Laboratory for Molecular Analysis of Higher Brain Function, RIKEN Center for Brain Science, Japan.
³ Brain Image Analysis Unit, RIKEN Center for Brain Science, Japan.
⁴ Department of Stereotactic and Functional Neurosurgery, Medical Center of the University of Freiburg, Freiburg, Germany, Breisacher Straße 64, 79106, Freiburg Im Breisgau, Germany; AG Stereotaxy and Interventional Neurosciences (SIN), Department of Stereotactic and Functional Neurosurgery, Medical Center of the University of Freiburg, Freiburg, Germany, Breisacher Straße 64, 79106, Freiburg Im Breisgau, Germany.
⁵ Department of Stereotactic and Functional Neurosurgery, Medical Center of the University of Freiburg, Freiburg, Germany, Breisacher Straße 64, 79106, Freiburg Im Breisgau, Germany; Medical Faculty of the University of Freiburg, Breisacher Str. 153, 79110, Freiburg Im Breisgau, Germany.
⁶ Department of Stereotactic and Functional Neurosurgery, Medical Center of the University of Freiburg, Freiburg, Germany, Breisacher Straße 64, 79106, Freiburg Im Breisgau, Germany; Medical Faculty of the University of Freiburg, Breisacher Str. 153, 79110, Freiburg Im Breisgau, Germany; Fraunhofer Institute for Laser Technology (ILT), Aachen, Germany.
⁷ Department of Stereotactic and Functional Neurosurgery, Medical Center of the University of Freiburg, Freiburg, Germany, Breisacher Straße 64, 79106, Freiburg Im Breisgau, Germany; Medical Faculty of the University of Freiburg, Breisacher Str. 153, 79110, Freiburg Im Breisgau, Germany; Department of Diagnostic and Interventional Radiology, Medical Physics, Medical Center - University of Freiburg, Killianstrasse 5a, 79106, Freiburg, Germany. Electronic address: [email protected].

PMID: 37028755
DOI: 10.1016/j.brs.2023.03.012

Abstract

Background: Understanding prefrontal cortex projections to diencephalic-mesencephalic junction (DMJ), especially to subthalamic nucleus (STN) and ventral mesencephalic tegmentum (VMT) helps our comprehension of Deep Brain Stimulation (DBS) in major depression (MD) and obsessive-compulsive disorder (OCD). Fiber routes are complex and tract tracing studies in non-human primate species (NHP) have yielded conflicting results. The superolateral medial forebrain bundle (slMFB) is a promising target for DBS in MD and OCD. It has become a focus of criticism owing to its name and its diffusion weighted-imaging based primary description.

Objective: To investigate DMJ connectivity in NHP with a special focus on slMFB and the limbic hyperdirect pathway utilizing three-dimensional and data driven techniques.

Methods: We performed left prefrontal adeno-associated virus - tracer based injections in the common marmoset monkey (n = 52). Histology and two-photon microscopy were integrated into a common space. Manual and data driven cluster analyses of DMJ, subthalamic nucleus and VMT together, followed by anterior tract tracing streamline (ATTS) tractography were deployed.

Results: Typical pre- and supplementary motor hyperdirect connectivity was confirmed. The advanced tract tracing unraveled the complex connectivity to the DMJ. Limbic prefrontal territories directly projected to the VMT but not STN.

Discussion: Intricate results of tract tracing studies warrant the application of advanced three-dimensional analyses to understand complex fiber-anatomical routes. The applied three-dimensional techniques can enhance anatomical understanding also in other regions with complex fiber anatomy.

Conclusion: Our work confirms slMFB anatomy and enfeebles previous misconceptions. The rigorous NHP approach strengthens the role of the slMFB as a target structure for DBS predominantly in psychiatric indications like MD and OCD.

Keywords: Common marmoset; Deep brain stimulation; Depression; OCD; Prefrontal cortex anatomy; Subcortical projection pathways.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Callithrix
Deep Brain Stimulation* / methods
Medial Forebrain Bundle
Mesencephalon
Subthalamic Nucleus*