Zu den Inhalten springen

Division of Stereotactic and Functional Neurosurgery

Research

Scientific Background

Major depressive disorder (MDD, or depression) is a global epidemic with a lifetime prevalence of 15%1, and symptoms including low motivation, anhedonia, social withdrawal and suicidal ideation2,3. The diverse symptoms, triggers and possible biological underpinnings explain the multiple research strategies and numerous theories concerning the etiology of MDD4–6.

Conventional anti-depressant therapies offer symptomatic relief to the majority of the diagnosed patients7; however, about 25-30% of MDD patients remain refractory and are eligible for experimental therapies, including Deep Brain Stimulation (DBS) 8. Clinical trials headed by Profs Coenen and Schläpfer (Department of Stereotactic and Functional Neurosurgery, University Hospital Freiburg) looking at DBS of the supero-lateral MFB produced fast and long-term anti-depressant effects with 75% responders and sustained remission in 50% of the previously treatment resistant patients, and this state of remission was present even after the first 4 year follow-up 9–11.

The Laboratory of Stereotaxy and Interventional Neurosciences (SIN) is the pre-clinical wing of the Department of Stereotactic and Functional Neurosurgery, which explains the strong translational nature of our group’s research interest and direction.

The work in our laboratory focuses on the hypothesis that key symptoms observed in MDD (anhedonia and reduced motivation) are linked to dysfunctions in the reward/motivation circuitry. Key elements of this circuitry are the medial prefrontal (mPFC/ PrL), the nucleus accumbens (NAc), the ascending A10 mesocorticolimbic dopaminergic (mclDA) projections arising in the ventral tegmental area (VTA) and projecting to the mPFC and the NAc via the medial forebrain bundle (MFB). The mclDA pathway activity is regulated in multiple ways, including by glutamatergic input from the PFC, the lateral habenula (LHb)12, or the rostromedial tegmental nucleus (RMTg)13. Dopamine (DA) has been implicated in seminal symptoms of depression such as motivation and reward-driven behaviors14, and studies from affective neuroscience have strongly suggested that the mclDA component of the MFB is the neural substrate for positive emotional, euphoric behaviors supporting exploration, and controlling appetitive learning15.

Currently, MFB-DBS remains poorly understood and there is paucity of data on acute and chronic mechanisms and biological substrates. Our working hypothesis is that MFB-DBS, and other neuromodulatory modalities, exerts its anti-depressant action via modulation of inter-structural communication and molecular mechanisms within the reward/motivation network.

A related but separate research line pursued by the group has been the development of a large animal model (LAM) that serves as an experimental platform to test novel neuromodulatory strategies, including brain-interface-components. The LAM serves as an experimental tool for in-vivo, chronic functional testing of devices/ brain-interface-components which become candidates for medical/ therapeutic regulatory body approval.  

Over the years, the group has developed broad experimental skill sets, establishing collaborations with colleagues locally, nationally and internationally. We employ this synergy to study depression-like behavior in diverse pre-clinical models of MDD, neuromodulation, epigenetics/ transciptomics, electrophysiology, non-invasive in vivo imaging using MRI and PET, and understanding the role of DA (and other neurotransmitters and modulators) in network activity control, synaptic transmission and plasticity of the limbic circuitry. We are also investigating the involvement of the glutamatergic signaling in the rapid antidepressant action of sleep deprivation, DBS and ketamine.

In summary, our work aims to give further insights into the mechanisms of action of MFB-DBS, and of other neuromodulatory modalities, by providing innovative data concerning inter-structural communication across the disease models. We are also investigating brain circuits and synaptic mechanisms involved in the regulation of mood and motivation-oriented behavior aiming to shed light on the molecular and cellular mechanisms of antidepressant therapy.

 

1.         WHO. Depression: fact sheet. www.who.int/mediacentre/factsheets/fs369/en/. (2017).

2.         Salk, R. H., Hyde, J. S. & Abramson, L. Y. Psychol. Bull. 143, 783–822 (2017).

3.         Belzung, C., Willner, P. & Philippot, P. Curr. Opin. Neurobiol. 30, 24–30 (2015).

4.         Liu, B., Liu, J., Wang, M., Zhang, Y. & Li, L. Front. Cell. Neurosci. 11, 305 (2017).

5.         Pariante, C. M. Eur. Neuropsychoph. J. Eur. Coll. Neuropsychoph. 27, 554–559 (2017).

6.         Jesulola, E., Micalos, P. & Baguley, I. J. Behav. Brain Res. 341, 79–90 (2018).

7.         Yang, Y., Wang, H., Hu, J. & Hu, H. Curr. Opin. Neurobiol. 48, 90–96 (2018).

8.         Bourdy, R. & Barrot, M. Trends Neurosci. 35, 681–690 (2012).

9.         Heshmati, M. & Russo, S. J. Curr. Behav. Neurosci. Rep. 2, 146–153 (2015).

10.       Berridge, K. C. & Kringelbach, M. L. Neuron 86, 646–664 (2015).

11.       Cipriani, A. et al. The Lancet doi:10.1016/S0140-6736(17)32802-7.

12.       Dandekar, M. P. et al. Mol. Psychiatry 23, 1094–1112 (2018).

13.       Schlaepfer, T. E. et al. Biol. Psychiatry 73, 1204–1212 (2013).

14.       Bewernick, B. H. et al. Brain Stimulat. 10, 664–671 (2017).

15.       Coenen, V. A. et al.  Neuropsychoph. doi:10.1038/s41386-019-0369-9 (2019).

Lab of Stereotaxy and Interventional Neuroscience

PD Dr. Máté Döbrössy

Group Leader

Department of Stereotactic and Functional Neurosurgery
University Medical Center Freiburg
Phone: +49  (0) 761 - 270 50360
Fax:       +49  (0) 761 - 270 50100
mate.dobrossy@uniklinik-freiburg.de

Prof. Dr. Volker Arnd Coenen

Medical Director