RESUMEN

Major depressive disorder (MDD) is prevalent with a high subjective and socio-economic burden. Despite the effectiveness of classical treatment methods, 20-30% of patients stay treatment-resistant. Deep Brain Stimulation of the superolateral branch of the medial forebrain bundle is emerging as a clinical treatment. The stimulation region (ventral tegmental area, VTA), supported by experimental data, points to the role of dopaminergic (DA) transmission in disease pathology. This work sets out to develop a workflow that will allow the performance of analyses on midbrain DA-ergic neurons and projections in subjects who have committed suicide. Human midbrains were retrieved during autopsy, formalin-fixed, and scanned in a Bruker MRI scanner (7T). Sections were sliced, stained for tyrosine hydroxylase (TH), digitized, and integrated into the Montreal Neurological Institute (MNI) brain space together with a high-resolution fiber tract atlas. Subnuclei of the VTA region were identified. TH-positive neurons and fibers were semi-quantitatively evaluated. The study established a rigorous protocol allowing for parallel histological assessments and fiber tractographic analysis in a common space. Semi-quantitative readings are feasible and allow the detection of cell loss in VTA subnuclei. This work describes the intricate workflow and first results of an investigation of DA anatomy in VTA subnuclei in a growing naturalistic database.

RESUMEN

Uncertainties concerning anatomy and function of cortico-subcortical projections have arisen during the recent years. 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's 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, n = 80) for long-range tractography and augmented this dataset with ex-vivo high resolution data (n = 1) 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-for the first time-are 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-as far as they can be discerned-appear 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.

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RESUMEN

Fiber tractography based on diffusion-weighted MRI provides a non-invasive characterization of the structural connectivity of the human brain at the macroscopic level. Quantification of structural connectivity strength is challenging and mainly reduced to "streamline counting" methods. These are however highly dependent on the topology of the connectome and the particular specifications for seeding and filtering, which limits their intra-subject reproducibility across repeated measurements and, in consequence, also confines their validity. Here we propose a novel method for increasing the intra-subject reproducibility of quantitative estimates of structural connectivity strength. To this end, the connectome is described by a large matrix in positional-orientational space and reduced by Principal Component Analysis to obtain the main connectivity "modes". It was found that the proposed method is quite robust to structural variability of the data.

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