Synopsis

The goal of this study is to investigate the anatomo-functional organization of the hyperdirect pathway between the subthalamic nucleus (STN) and the cortex in humans. We identified motor, limbic and associative areas of the whole cortex. We used DWI from 30 healthy subjects and probabilistic tractography between the STN and 39 cortical areas. The motor part of the hyperdirect pathway was found predominant compare to the limbic and above all the associative parts.

Introduction

The subthalamic nucleus (STN) is a critical component of normal motor function. It has become the main target for deep brain stimulation (DBS) in Parkinson’s disease patients to significantly improve motor functions in patients with advanced forms of the disease. While the underlying mechanism of action for DBS is still unknown, the potential modulation of white matter tracts connecting the surgical targets has become an active area of research¹.

The hyperdirect pathway is a direct excitatory connection from the cortex to the STN. While the motor part of the hyperdirect pathway has been extensively studied^2-5, the associative and limbic components are much less understood. Understanding the associative and limbic components of the hyperdirect pathway might help to minimize borders effects observed in some patients during DBS surgery and would improve DBS clinical results.

The aim of this study is to investigate the anatomo-functional organization of the hyperdirect pathway, and to focus on the associative and limbic cortical areas compared to the motor components.

Methods

The methodological pipeline is summarised in Fig. 1.

We used DWI acquired at 3T (1.25 mm isovoxel size) from 30 healthy subjects included and preprocessed in the Human Connectome Project (HCP)⁶.

Data were processed with MRtrix and we estimated the distribution of fiber orientations (FOD) present within each imaging voxel using the Constrained Spherical Deconvolution framework⁷. Probabilistic whole-brain tractography was run with the following parameters: 100 million tracks, step length of 0.1 mm, curvature threshold of 45°, minimum tract length of 6 mm, maximum tract length of 250 mm and fiber orientation distribution amplitude cut-off of 0.1. The spherical-deconvolution informed filtering of tractograms was applied to reduce the number of streamlines to 10 million to provide a biologically meaningful estimate of structural connection density by removing false positive tracts⁸.

78 tracts were extracted between 39 cortical areas (segmented using a Brodmann atlas) and the STN (segmented using our in-house 3D histological and deformable atlas of the human basal ganglia⁹).

Track-density maps were created to observe the cortical projections onto the STN¹⁰.

Results

Fig. 2 shows individual tractography reconstructions of three pathways between the STN and Brodmann areas in two subjects. The reconstructed tracts are symmetric and consistent with the expected anatomy^4,5. The tracks innervate the whole regions of interest.

Fig. 3 presents the track-density maps at the STN level for the three previous fibers bundles. We observe a topological organization of the motor connectivity. Connections between the area 6 and STN are slightly more medial than connections between the area 4 and STN.

Fig. 4 shows the average number of streamlines across the 30 healthy subjects. Motor areas have the highest number of connections with the STN while limbic areas and above all the associative ones have a lower connectivity strength with the STN. Limbic connectivity is more dominant in the right hemisphere than the left.

Conclusion

Our results on the connectivity between the cortex and STN using DWI data from 30 healthy subjects of the HCP show that the motor part of the hyperdirect pathway is much more predominant than the limbic part, while that the associative part is much more restricted.

It would be interesting to classify STN voxels based on their cortical connectivity densities.

Acknowledgements

The research leading to these results received funding from the programs "Institut des neurosciences translationnelles" ANR-10-IAIHU-06 and "Infrastructure d’avenir en Biologie Santé" ANR-11-INBS-0006.

SBS has been supported by the Bettencourt Schueller Foundation and by the National Agency for Research under the program "Investissements d’avenir" ANR-10-EQPX-15.

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